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CUBN variants cause proteinuria without kidney disease 2

Sensitizing pancreatic tumors to immunotherapy 3

Hypoxia drives protumor neutrophil activity 5

Microbiota-driven bile acid release in irritable bowel syndrome 6

JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight

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January 2020

This MonthCD4+ T cell response to human RSV infection p. 2

Journal of Clinical Investigation Consulting Editors

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j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 2 0 1

For the JCIEditorRexford S. Ahima

Deputy EditorsArturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli

Associate EditorsMark E. Anderson, Mary Y. Armanios, Nilofer S. Azad, Joel N. Blankson, William R. Bishai, Robert A. Brodsky, Peter A. Calabresi, Thomas L. Clemens, Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, Paul M. Hassoun, Maureen R. Horton, Elizabeth M. Jaffee, Mariana J. Kaplan, Marikki Laiho, Leo Luznik, Marcela V. Maus, Timothy H. Moran, Laszlo Nagy, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Jean-Pierre Raufman, Stuart C. Ray, Linda Smith Resar, Jeffrey D. Rothstein, Jonathan Schneck, Akrit S. Sodhi, Charlotte J. Sumner, Simeon I. Taylor, Robert G. Weiss, Sarah J. Wheelan, Marsha Wills-Karp

Editorial Advisory GroupPeter Agre, Carol W. Grieder, Diane E. Griffin, Paul B. Rothman, David Valle

BiostatisticianEliseo Guallar

Computational BiologistPatrick Cahan

Staff EditorsExecutive EditorSarah C. Jackson

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Editor at LargeUshma S. Neill

Editorial InternBouchra Taib

JCI This Month ISSN 2380-3029 (print)ISSN 2380-3037 (online)For the full JCI online: jci.me/130/1

This MonthJanuary 2020

Contact the JCI and JCI Insight2015 Manchester Road, Ann Arbor, Michigan 48104, USAPhone: 734.222.6050Email: staff@the-jci.org (JCI); staff@insight.jci.org (JCI Insight)

The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation and JCI Insight. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

(ASCI) indicates corresponding authors who are ASCI members.

Akrit Sodhi, MD, PhD, Associate Editor, is an associate professor of oph-thalmology and holds the Branna and Irving Sisenwein Professorship in Oph-thalmology at the Johns Hopkins Wilmer Eye Institute. Dr. Sodhi’s research interests center on the role of the tran-scription factor hypoxia-inducible factor (HIF) in ocular disease. His laboratory investigates the role of HIF and HIF- regulated gene products in the patho-physiology of ischemic retinopathies, retinal degeneration, and ocular tumors, with the goal of identifying novel bio-markers and therapeutic targets for the diagnosis, prevention, and/or treatment of these vision-threatening diseases.

Publication highlights Sodhi A, Ma T, Menon D, Deshpande M, Jee K, Dinabandhu A, Vancel J, Lu D, Mon-taner S. Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema. J Clin Invest. 2019;129(11):4593–4608.

Jee K, Rodrigues M, Kashiwabuchi F, Applewhite BP, Han I, Lutty G, Goldberg MF, Semenza GL, Montaner S, Sodhi A. Expression of the angiogenic mediator, angio-poietin-like 4, in the eyes of patients with proliferative sickle retinopathy. PLoS One. 2017;12(8):e0183320.

Hu K, Babapoor-Farrokhran S, Rodrigues M, Deshpande M, Puchner M, Kashiwabuchi F, Hassan SJ, Asnaghi L, Handa JT, Merbs S, Eberhart CG, Semenza GL, Montaner S, Sodhi A. Hypoxia-inducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melano-ma. Oncotarget. 2016;7(7):7816–7828.

Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X, Rodrigues M, Kashi-wabuchi F, Ma T, Hu K, Deshpande M, Daoud Y, Solomon S, Wenick A, Lutty G, Semenza GL, Montaner S, Sodhi A. Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc Natl Acad Sci U S A. 2015;112(23):E3030–E3039.

The JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.

Featured Editor

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 2 02

research

Editor’s picks

on the jci cover clinical medicine

Tracking CD4+ T cell activity, recruitment, and reactivity in RSV-infected volunteersRespiratory syncytial virus (RSV) infection can produce severe disease in infants and the elderly, and the virus remains capable of reinfecting individuals throughout life. CD4+ T cells play an important role in RSV clearance, possibly through interaction with lung-resident T cell populations. However, little is known about these cells’ dynamic response to infection. In this issue of the JCI, Aleks Guvenel et al. inoculated 49 healthy volunteers with RSV and monitored T cell activation, proliferation, and recruitment to the airways. CD4+ T cell activation and proliferation were elevated in blood and bronchoalveolar lavage samples obtained from the 29 individuals who developed RSV infection compared with volunteers who resisted infection. Substantial interindividual variation in bronchial CD4+ T cell activation did not correlate with viral load; rather, CXCL10 expression appeared to coordinate CD4+ T cell responses in RSV-infected volunteers. In all study participants, CD4+ T cells responded to RSV’s F glycoprotein, a major antigen in current RSV vaccine candidates. However, a large proportion of volunteers also displayed reactivity to the G glycoprotein, suggesting that including a G protein antigen in RSV vaccines may enhance CD4+ responses. Ongoing characterization of RSV-specific immune responses in the setting of active disease will likely provide powerful insight into effective vaccine development. The cover image is an artistic rendering of RSV, with fusion proteins and attachment proteins depicted in purple and red, respectively (image credit: Kateryna Kon/Shutterstock).

Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infectionAleks Guvenel, Agnieszka Jozwik, Stephanie Ascough, Seng Kuong Ung, Suzanna Paterson, Mohini Kalyan, Zoe Gardener, Emma Bergstrom, Satwik Kar, Maximillian S. Habibi, Allan Paras, Jie Zhu, Mirae Park, Jaideep Dhariwal, Mark Almond, Ernie H.C. Wong, Annemarie Sykes, Jerico Del Rosario, Maria-Belen Trujillo-Torralbo, Patrick Mallia, John Sidney, Bjoern Peters, Onn Min Kon, Alessandro Sette, Sebastian L. Johnston, Peter J. Openshaw, and Christopher Chiu http://jci.me/131696

Humans with CUBN variants retain normal renal function despite proteinuriaProteinuria, or abnormal protein levels in urine, occurs when the glomerular filtration barrier is compromised. Individuals with proteinuria are considered to be at higher risk for developing chronic kidney disease. However, in this issue of the JCI, Matias Simons and colleagues characterized 39 patients in whom chronic proteinuria appears to be nonpathogenic. The patients harbor biallelic variants in the CUBN gene, which encodes a protein uptake receptor expressed in the intestines and proximal tubules. Although the patients were diagnosed with chronic, albumin-predominant proteinuria in early childhood, their renal function remained normal into adulthood. In the accompanying Commen-tary, Andrew Beenken, Jonathan Barasch, and Ali Gharavi discuss these insights into the clinical implications of proteinuria, indicating the need for further investigation of proteinuria phenotypes and causes in human disease.

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal functionMathilda Bedin, Olivia Boyer, Aude Servais, Yong Li, Laure Villoing-Gaudé, Marie-Josephe Tête, Alexandra Cambier, Julien Hogan, Veronique Baudouin, Saoussen Krid, Albert Bensman, Florie Lammens, Ferielle Louillet, Bruno Ranchin, Cecile Vigneau, Iseline Bouteau, Corinne Isnard-Bagnis, Christoph J. Mache, Tobias Schäfer, Lars Pape, Markus Gödel, Tobias B. Huber, Marcus Benz, Günter Klaus, Matthias Hansen, Kay Latta, Olivier Gribouval, Vincent Morinière, Carole Tournant, Maik Grohmann, Elisa Kuhn, Timo Wagner, Christine Bole-Feysot, Fabienne Jabot-Hanin, Patrick Nitschké, Tarunveer S. Ahluwalia, Anna Köttgen, Christian Brix Folsted Andersen, Carsten Bergmann, Corinne Antignac, and Matias Simons http://jci.me/129937

Related CommentaryNot all proteinuria is created equalAndrew Beenken, Jonathan M. Barasch, and Ali G. Gharavi (ASCI) http://jci.me/133250

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 2 0 3

JCI | Research: Editor’s picks

0phthalmology

oncology

Hexosamine biosynthesis contributes to immune evasion of pancreatic ductal adenocarcinomaPancreatic ductal adenocarcinoma (PDAC) is often unresponsive to immune checkpoint– targeting therapies due to a robust immunosuppressive tumor microenvironment (TME). While strategies targeting the TME stroma risk triggering tumor metastasis, modifying the TME extracellular matrix may be a way to improve immune infiltration. Nikita Sharma and colleagues hypothesized that the hexosamine biosynthesis pathway provides essential support to extracellular matrix formation and immunosuppression in PDAC tumors. They demonstrated that inhibiting this pathway using a small molecule glutamine analog led to pancreatic tumor regression and decreased metastasis in mouse models. The glutamine analog also induced extracellular matrix remodeling and altered the secretion of tumor-promoting cytokines. In mice, combining the glutamine analog with anti-PD1 Ab sensitized pancreatic tumors to checkpoint inhibitor therapy in a T cell–dependent manner. In the accompanying Commentary, Won Jin Ho and Elizabeth Jaffee discuss targeting the hexosamine biosynthesis pathway as a strategy for overcoming immune evasion in PDAC tumors.

mtDNA depletion syndrome with optic atrophy driven by SSBP1 mutations

The clinical manifestations of mitochondrial dysfunction are highly variable and are typically driven by mutations in multiple mitochondrial genes. Mutations affecting mitochondrial maintenance genes underlie mtDNA depletion syndromes (MDSs), which are not usually associated with optic neuropathy and do not typically affect adult life. In this issue, two studies report the identification of heterozygous pathogenic mutations in mitochondrial single-strand binding protein 1 (SSBP1) as single-gene drivers of an MDS that presents with optic atrophy

in addition to a spectrum of other pathologies. Working independently, Piro-Mégy et al. and Del Dotto et al. characterized optic atrophy as the predominant clinical symptom in patients with SSBP1 mutations (see the associated image), but also noted nephropathy, deafness, and myopathy in multiple probands. Further, the groups revealed that the severity of mitochondrial dysfunction mirrored the degree of impaired mtDNA replication in patient-derived fibroblasts. In the accompanying Commen-tary, Lina Zelinger and Anand Swaroop discuss the identification of SSBP1 as a mitochondrial maintenance gene and emerging insights into the variable clinical presentation of mitochondrial disorders.

Related ResearchDominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathyCamille Piro-Mégy, Emmanuelle Sarzi, Aleix Tarrés-Solé, Marie Péquignot, Fenna Hensen, Mélanie Quilès, Gaël Manes, Arka Chakraborty, Audrey Sénéchal, Béatrice Bocquet, Chantal Cazevieille, Agathe Roubertie, Agnès Müller, Majida Charif, David Goudenège, Guy Lenaers, Helmut Wilhelm, Ulrich Kellner, Nicole Weisschuh, Bernd Wissinger, Xavier Zanlonghi, Christian Hamel, Johannes N. Spelbrink, Maria Sola, and Cécile Delettre http://jci.me/128513

SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorderValentina Del Dotto, Farid Ullah, Ivano Di Meo, Pamela Magini, Mirjana Gusic, Alessandra Maresca, Leonardo Caporali, Flavia Palombo, Francesca Tagliavini, Evan Harris Baugh, Bertil Macao, Zsolt Szilagyi, Camille Peron, Margaret A. Gustafson, Kamal Khan, Chiara La Morgia, Piero Barboni, Michele Carbonelli, Maria Lucia Valentino, Rocco Liguori, Vandana Shashi, Jennifer Sullivan, Shashi Nagaraj, Mays El-Dairi, Alessandro Iannaccone, Ioana Cutcutache, Enrico Bertini, Rosalba Carrozzo, Francesco Emma, Francesca Diomedi-Camassei, Claudia Zanna, Martin Armstrong, Matthew Page, Nicholas Stong, Sylvia Boesch, Robert Kopajtich, Saskia Wortmann, Wolfgang Sperl, Erica E. Davis, William C. Copeland, Marco Seri, Maria Falkenberg, Holger Prokisch, Nicholas Katsanis, Valeria Tiranti, Tommaso Pippucci, and Valerio Carelli http://jci.me/128514

Related CommentarySSBP1 faux pas in mitonuclear tango causes optic neuropathyLina Zelinger and Anand Swaroop http://jci.me/132532

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapyNikita S. Sharma, Vineet K. Gupta, Vanessa T. Garrido, Roey Hadad, Brittany C. Durden, Kousik Kesh, Bhuwan Giri, Anthony Ferrantella, Vikas Dudeja, Ashok Saluja, and Sulagna Banerjee http://jci.me/127515

Related CommentaryDisrupting a converging metabolic target turns up the immunologic-heat in pancreatic tumorsWon Jin Ho and Elizabeth M. Jaffee http://jci.me/133685

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 2 04

JCI | Research: Editor’s picks

Characterizing unconventional T cell repertoires in human lungs during tuberculosis infection

Cold-sensitive brown adipocytes interconvert between low- and high-thermogenic subpopulations

metabolism

immunology

Donor-unrestricted T cells (DURTs) and γδ T cells are specialized immune cells that, unlike conventional T cells, can recognize nonproteinaceous antigens. These antigens are often pathogen-derived lipids or small molecules that represent attractive targets for vaccine development. With the long-term goal of improving tuberculosis vaccination strategies, Paul Ogongo and colleagues sequenced DURT and δγ T cell receptor (δγ TCR) repertoires in human lung granulomas and blood samples during tuberculosis infection with or without HIV coinfection. Although DURT populations were diminished in the peripheral blood of tuberculosis-infected individuals, DURT repertoires were preserved in infected lungs regardless of HIV status, suggesting that HIV infection does not deplete these tissue-resident subsets. Additionally, δ-TCR repertoires in the tuberculosis-infected lung were markedly skewed, reflecting the tissue-resident nature of γδ T cells. In the accompanying Commentary, Corinna Kulicke, Deborah Lewinsohn, and David Lewinsohn discuss the implications of these unconventional T cell subsets at the site of disease and potential therapeutic indications.

Brown adipocytes are distinguished from white adipocytes by their thermogenic properties, high numbers of mitochondria, and expression of uncoupling protein 1 (UCP1). Although brown adipose tissue is typically considered a homogenous population of cells, recent work by Anying Song and colleagues challenges this assumption. Using multiple labeling systems, single-cell sequencing, and 3D tissue imaging, the authors identified a low-thermogenic brown adipocyte subpopu-lation coexisting with classic high-thermogenic brown adipocytes, observing that cold exposure substantially increased the proportion of the high-thermogenic subpopulation. Pulse-chase experiments supported their interpretation that temperature drives brown adipocytes to convert between the two subpopulations. Further characterization revealed fewer mitochondria as well as decreased Ucp1 and adiponectin (Adipoq) expression in low-thermogenic compared with high-thermogenic brown adipocytes. Interconversion declined with age, as cold exposure induced substantially fewer high-thermogenic

brown adipocytes in 30-week-old versus 10-week-old mice (see the associated images). Yasuo Oguri and Shingo Kajimura’s accompanying Commentary details the evidence for plasticity in the thermogenic functions of brown adipocytes.

Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissueAnying Song, Wenting Dai, Min Jee Jang, Leonard Medrano, Zhuo Li, Hu Zhao, Mengle Shao, Jiayi Tan, Aimin Li, Tinglu Ning, Marcia M. Miller, Brian Armstrong, Janice M. Huss, Yi Zhu, Yong Liu, Viviana Gradinaru, Xiwei Wu, Lei Jiang, Philipp E. Scherer, and Qiong A. Wang http://jci.me/129167

Related CommentaryCellular heterogeneity in brown adipose tissueYasuo Oguri and Shingo Kajimura http://jci.me/133786

Differential skewing of donor-unrestricted and γδ T cell repertoires in tuberculosis-infected human lungsPaul Ogongo, Adrie J.C. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, and Samuel M. Behar http://jci.me/130711

Related CommentaryClonal enrichments of Vδ2– γδ T cells in Mycobacterium tuberculosis–infected human lungsCorinna A. Kulicke, Deborah A. Lewinsohn, and David M. Lewinsohn http://jci.me/133119

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 2 0 5

JCI | Research: Editor’s picks

Immune and glycosylation defects in patients with XMEN immunodeficiency syndrome

immunology

Hypoxia coordinates the protumor and antitumor functions of polymorphonuclear neutrophilsPolymorphonuclear neutrophils (PMNs) appear to play divergent roles in tumor development, promoting proliferation and metastasis in some contexts and mediating antitumor effects in others. The tumor microenviron-ment likely influences PMN phenotypes, but the determining characteristics have remained unclear. Karim Mahiddine and colleagues report that tumor oxygenation profoundly impacts the direct interactions between PMNs and tumor cells. They alleviated tumor hypoxia in a model of uterine cancer by housing mice in hyperoxic conditions. Compared with ambient conditions, hyperoxia reduced PMN recruitment to uterine tumors (PMNs highlighted by arrowheads in the accompanying images). Hyperoxia also increased the PMNs’ antitumor activity and abrogated their ability to promote tumor cell proliferation, suggesting that relief of hypoxia drives a shift toward antitumor phenotypes. The findings implicate hypoxia in driving PMN recruitment to tumors as well as promoting proproliferative PMN functions, laying the groundwork for application in cancer therapy.

XMEN disease is a rare immunodeficiency syndrome caused by loss-of-function mutations in the X-linked magnesium transporter gene MAGT1. MAGT1 participates in glycosylation processes that are known to be critical for lymphocyte function, but the consequences of MAGT1 defects in human lymphocytes are unclear. Juan Ravell, Mami Matsuda-Lennikov, and colleagues performed deep immunophenotyping of PBMCs from 23 patients with XMEN disease to develop an algorithm that identifies individuals with XMEN on the basis of the abundance of 2 naive B cell populations. Proteomics analyses revealed a glycosylation defect that alters surface expression of several T cell receptors. Transfecting patients’ PBMCs with WT MAGT1 corrected glycosylation defects, suggesting that a gene therapy approach may rescue some immune functions in patients with XMEN disease. In the accompanying Commentary, Hudson Freeze describes the importance of clarifying the etiology and diagnosis of XMEN disease.

Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophilsKarim Mahiddine, Adam Blaisdell, Stephany Ma, Amandine Créquer-Grandhomme, Clifford A. Lowell, and Adrian Erlebacher http://jci.me/130952

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN diseaseJuan C. Ravell, Mami Matsuda-Lennikov, Samuel D. Chauvin, Juan Zou, Matthew Biancalana, Sally J. Deeb, Susan Price, Helen C. Su, Giulia Notarangelo, Ping Jiang, Aaron Morawski, Chrysi Kanellopoulou, Kyle Binder, Ratnadeep Mukherjee, James T. Anibal, Brian Sellers, Lixin Zheng, Tingyan He, Alex B. George, Stefania Pittaluga, Astin Powers, David E. Kleiner, Devika Kapuria, Marc Ghany, Sally Hunsberger, Jeffrey I. Cohen, Gulbu Uzel, Jenna Bergerson, Lynne Wolfe, Camilo Toro, William Gahl, Les R. Folio, Helen Matthews, Pam Angelus, Ivan K. Chinn, Jordan S. Orange, Claudia M. Trujillo-Vargas, Jose Luis Franco, Julio Orrego-Arango, Sebastian Gutiérrez-Hincapié, Niraj Chandrakant Patel, Kimiyo Raymond, Turkan Patiroglu, Ekrem Unal, Musa Karakukcu, Alexandre G.R. Day, Pankaj Mehta, Evan Masutani, Suk S. De Ravin, Harry L. Malech, Grégoire Altan-Bonnet, V. Koneti Rao, Matthias Mann, and Michael J. Lenardo http://jci.me/131116

Related CommentaryXMEN: welcome to the glycosphereHudson H. Freeze http://jci.me/134240

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JCI | Research: Editor’s picks

gastroenterology

Understanding immune toxicity triggered by immune checkpoint inhibitors

review

Immunotherapies revolutionized our approach to cancer treatment but remain associated with a high incidence of immune-related adverse events (irAEs). Immune checkpoint inhibitors (ICIs) targeting CTLA-4, PD-1, and PD-L1 can unleash cytotoxic T cell activity against tumor cells, and their cytotoxic effects can also be turned against the body, driving inflammatory toxicity that can resemble spontaneous autoimmune disease. In this issue, a Review by Michael Dougan and Massimo Pietropaolo describes the irAEs associated with ICIs and details clinical evidence that provides clues to irAE pathogenesis. They speculate that the

viewpoint

Fighting fire with fire: medications to combat opioid addictionA subset of patients who are prescribed opioid pain medications will develop opioid addiction, the result of changes in brain circuits that regulate motivation, decision-making, and mood. In these individuals, abrupt cessation of opioid use triggers physiological withdrawal in addition to compulsive drug-seeking responses and negative emotional states. In this issue, a Viewpoint by Nora Volkow and Carlos Blanco of the National Institute on Drug Abuse explains that the distinction between physical dependence on opioids and opioid addiction has important implications for successfully treating patients with opioid use disorder (OUD). Medications for OUD (MOUDs) comprise a variety of opioid receptor agonists and antagonists that can help control opioid craving and withdrawal symptoms. The use of MOUDs in treating OUD is not without critique, as some of these medications also have rewarding properties and abuse potential. However, Volkow and Blanco argue that MOUDs are among the most effective interventions for opioid use disorder and, with careful prescribing, may be important weapons for fighting the ongoing opioid epidemic.

Medications for opioid use disorders: clinical and pharmacological considerationsNora D. Volkow and Carlos Blanco http://jci.me/134708

Intestinal Clostridia species boost bile acids in patients with diarrhea-predominant IBSMany patients with diarrhea-predominant irritable bowel syndrome (IBS-D) excrete excessive fecal bile acids, which are linked with worsening symptoms. Ling Zhao, Wei Yang, and colleagues investigated a potential interaction between fecal bile acid levels, IBS-D, and the gut microbiome. In a cohort of 290 IBS-D patients, 24.5% exhibited both excessive bile acid excretion and an increase in bile acid–transforming bacterial species, including Clostridia. In these patients, a Clostridia-rich microbiome and elevated bile acids were inversely correlated with serum concentrations of FGF15, an inhibitor of bile acid synthesis. Experiments conducted in mice revealed that Clostridia-transformed bile acids suppress FGF19, disrupting FXR-mediated regulation of bile acid production. In the accompanying Commentary, Julian Walters and Julian Marchesi discuss the rationale for developing clinical interventions targeting Clostridia-rich microbiomes in IBS-D.

A Clostridia-rich microbiota enhances bile acid excretion in diarrhea-predominant irritable bowel syndromeLing Zhao, Wei Yang, Yang Chen, Fengjie Huang, Lin Lu, Chengyuan Lin, Tao Huang, Ziwan Ning, Lixiang Zhai, Linda L.D. Zhong, Waiching Lam, Zhen Yang, Xuan Zhang, Chungwah Cheng, Lijuan Han, Qinwei Qiu, Xiaoxiao Shang, Runyue Huang, Haitao Xiao, Zhenxing Ren, Dongfeng Chen, Silong Sun, Hani El-Nezami, Zongwei Cai, Aiping Lu, Xiaodong Fang, Wei Jia, and Zhaoxiang Bian http://jci.me/130976

Related CommentaryChronic diarrhea, bile acids, and ClostridiaJulian R.F. Walters and Julian R. Marchesi http://jci.me/133117

mechanisms underlying irAEs provide clues to developing safer therapies as well as better treatment of autoimmune diseases. The accompanying image depicts the glycan sequences of various anti–CTLA-4, anti–PD-1, and anti–PD-L1 mAbs; varying mAb design may be one method of engineering reduced risk of irAEs into ICIs.

Time to dissect the autoimmune etiology of cancer antibody immunotherapyMichael Dougan and Massimo Pietropaolo http://jci.me/131194

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Current research articles

agingBubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndromeCynthia J. Sieben, Karthik B. Jeganathan, Grace G. Nelson, Ines Sturmlechner, Cheng Zhang, Willemijn H. van Deursen, Bjorn Bakker, Floris Foijer, Hu Li, Darren J. Baker, and Jan M. van Deursen http://jci.me/126863

autoimmunityAutoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progressionAlice E. Wiedeman, Virginia S. Muir, Mario G. Rosasco, Hannah A. DeBerg, Scott Presnell, Bertrand Haas, Matthew J. Dufort, Cate Speake, Carla J. Greenbaum, Elisavet Serti, Gerald T. Nepom, Gabriele Blahnik, Anna M. Kus, Eddie A. James, Peter S. Linsley, and S. Alice Long http://jci.me/126595

clinical medicineHuman C-terminal CUBN variants associate with chronic proteinuria and normal renal function p. 2Mathilda Bedin, Olivia Boyer, Aude Servais, Yong Li, Laure Villoing-Gaudé, Marie-Josephe Tête, Alexandra Cambier, Julien Hogan, Veronique Baudouin, Saoussen Krid, Albert Bensman, Florie Lammens, Ferielle Louillet, Bruno Ranchin, Cecile Vigneau, Iseline Bouteau, Corinne Isnard-Bagnis, Christoph J. Mache, Tobias Schäfer, Lars Pape, Markus Gödel, Tobias B. Huber, Marcus Benz, Günter Klaus, Matthias Hansen, Kay Latta, Olivier Gribouval, Vincent Morinière, Carole Tournant, Maik Grohmann, Elisa Kuhn, Timo Wagner, Christine Bole-Feysot, Fabienne Jabot-Hanin, Patrick Nitschké, Tarunveer S. Ahluwalia, Anna Köttgen, Christian Brix Folsted Andersen, Carsten Bergmann, Corinne Antignac, and Matias Simons http://jci.me/129937

Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection p. 2Aleks Guvenel, Agnieszka Jozwik, Stephanie Ascough, Seng Kuong Ung, Suzanna Paterson, Mohini Kalyan, Zoe Gardener, Emma Bergstrom, Satwik Kar, Maximillian S. Habibi, Allan Paras, Jie Zhu, Mirae Park, Jaideep Dhariwal, Mark Almond, Ernie H.C. Wong, Annemarie Sykes, Jerico Del Rosario, Maria-Belen Trujillo-Torralbo, Patrick Mallia, John Sidney, Bjoern Peters, Onn Min Kon, Alessandro Sette, Sebastian L. Johnston, Peter J. Openshaw, and Christopher Chiu http://jci.me/131696

endocrinologyChemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonationMatthew J. Taylor, Matthew R. Ullenbruch, Emily C. Frucci, Juilee Rege, Mark S. Ansorge, Celso E. Gomez-Sanchez, Salma Begum, Edward Laufer, David T. Breault, and William E. Rainey http://jci.me/127429

Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosisAnh-Thu N. Lam, Melis A. Aksit, Briana Vecchio-Pagan, Celeste A. Shelton, Derek L. Osorio, Arianna F. Anzmann, Loyal A. Goff, David C. Whitcomb, Scott M. Blackman, and Garry R. Cutting (ASCI) http://jci.me/129833

gastroenterologyTrypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H

Fu Gui, Yuebo Zhang, Jianhua Wan, Xianbao Zhan, Yao Yao, Yinghua Li, Ashley N. Haddock, Ji Shi, Jia Guo, Jiaxiang Chen, Xiaohui Zhu, Brandy H. Edenfield, Lu Zhuang, Cheng Hu, Ying Wang, Debabrata Mukhopadhyay, Evette S. Radisky, Lizhi Zhang, Aurelia Lugea, Stephen J. Pandol, Yan Bi, and Baoan Ji http://jci.me/130172

A Clostridia-rich microbiota enhances bile acid excretion in diarrhea-predominant irritable bowel syndrome p. 6Ling Zhao, Wei Yang, Yang Chen, Fengjie Huang, Lin Lu, Chengyuan Lin, Tao Huang, Ziwan Ning, Lixiang Zhai, Linda L.D. Zhong, Waiching Lam, Zhen Yang, Xuan Zhang, Chungwah Cheng, Lijuan Han, Qinwei Qiu, Xiaoxiao Shang, Runyue Huang, Haitao Xiao, Zhenxing Ren, Dongfeng Chen, Silong Sun, Hani El-Nezami, Zongwei Cai, Aiping Lu, Xiaodong Fang, Wei Jia, and Zhaoxiang Bian http://jci.me/130976

hematologyChronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signalingHeather A. Himburg, Martina Roos, Tiancheng Fang, Yurun Zhang, Christina M. Termini, Lauren Schlussel, Mindy Kim, Amara Pang, Jenny Kan, Liman Zhao, Hyung Suh, Joshua P. Sasine, Gopal Sapparapu, Peter M. Bowers, Gary Schiller, and John P. Chute (ASCI) http://jci.me/129061

Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemiaVania Manolova, Naja Nyffenegger, Anna Flace, Patrick Altermatt, Ahmet Varol, Cédric Doucerain, Hanna Sundstrom, and Franz Dürrenberger http://jci.me/129382

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Current research articles

immunologyGut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune responseMireia Uribe-Herranz, Stavros Rafail, Silvia Beghi, Luis Gil-de-Gómez, Ioannis Verginadis, Kyle Bittinger, Sergey Pustylnikov, Stefano Pierini, Renzo Perales-Linares, Ian A. Blair, Clementina A. Mesaros, Nathaniel W. Snyder, Frederic Bushman, Constantinos Koumenis, and Andrea Facciabene http://jci.me/124332

Differential skewing of donor-unrestricted and γδ T cell repertoires in tuberculosis-infected human lungs p. 4Paul Ogongo, Adrie J.C. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, and Samuel M. Behar http://jci.me/130711

Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils p. 5Karim Mahiddine, Adam Blaisdell, Stephany Ma, Amandine Créquer-Grandhomme, Clifford A. Lowell, and Adrian Erlebacher http://jci.me/130952

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease p. 5Juan C. Ravell, Mami Matsuda-Lennikov, Samuel D. Chauvin, Juan Zou, Matthew Biancalana, Sally J. Deeb, Susan Price, Helen C. Su, Giulia Notarangelo, Ping Jiang, Aaron Morawski, Chrysi Kanellopoulou, Kyle Binder, Ratnadeep Mukherjee, James T. Anibal, Brian Sellers, Lixin Zheng, Tingyan He, Alex B. George, Stefania Pittaluga, Astin Powers, David E. Kleiner, Devika Kapuria, Marc Ghany, Sally Hunsberger, Jeffrey I. Cohen, Gulbu Uzel, Jenna Bergerson, Lynne Wolfe, Camilo Toro, William Gahl, Les R. Folio, Helen Matthews, Pam Angelus, Ivan K. Chinn, Jordan S. Orange, Claudia M. Trujillo-Vargas, Jose Luis Franco, Julio Orrego-Arango, Sebastian Gutiérrez-Hincapié, Niraj Chandrakant Patel, Kimiyo Raymond, Turkan Patiroglu, Ekrem Unal, Musa Karakukcu, Alexandre G.R. Day, Pankaj Mehta, Evan Masutani, Suk S. De Ravin, Harry L. Malech, Grégoire Altan-Bonnet, V. Koneti Rao, Matthias Mann, and Michael J. Lenardo http://jci.me/131116

infectious diseaseEpidermal hepcidin is required for neutrophil response to bacterial infectionMariangela Malerba, Sabine Louis, Sylvain Cuvellier, Srikanth Mairpady Shambat, Camille Hua, Camille Gomart, Agnès Fouet, Nicolas Ortonne, Jean-Winoc Decousser, Annelies S. Zinkernagel, Jacques R.R. Mathieu, and Carole Peyssonnaux http://jci.me/126645

Quadrivalent VesiculoVax vaccine protects nonhuman primates from viral-induced hemorrhagic fever and deathRobert W. Cross, Rong Xu, Demetrius Matassov, Stefan Hamm, Theresa E. Latham, Cheryl S. Gerardi, Rebecca M. Nowak, Joan B. Geisbert, Ayuko Ota-Setlik, Krystle N. Agans, Amara Luckay, Susan E. Witko, Lena Soukieh, Daniel J. Deer, Chad E. Mire, Heinz Feldmann, Christian Happi, Karla A. Fenton, John H. Eldridge, and Thomas W. Geisbert http://jci.me/131958

inflammationEpithelial membrane protein 2 governs transepithelial migration of neutrophils into the airspaceWan-Chi Lin, Kymberly M. Gowdy, Jennifer H. Madenspacher, Rachel L. Zemans, Kazuko Yamamoto, Miranda Lyons-Cohen, Hideki Nakano, Kyathanahalli Janardhan, Carmen J. Williams, Donald N. Cook, Joseph P. Mizgerd, and Michael B. Fessler (ASCI) http://jci.me/127144

GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infectionsMagdalena B. Flak, Duco S. Koenis, Agua Sobrino, James Smith, Kimberly Pistorius, Francesco Palmas, and Jesmond Dalli http://jci.me/131609

metabolismLow- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue p. 4Anying Song, Wenting Dai, Min Jee Jang, Leonard Medrano, Zhuo Li, Hu Zhao, Mengle Shao, Jiayi Tan, Aimin Li, Tinglu Ning, Marcia M. Miller, Brian Armstrong, Janice M. Huss, Yi Zhu, Yong Liu, Viviana Gradinaru, Xiwei Wu, Lei Jiang, Philipp E. Scherer, and Qiong A. Wang http://jci.me/129167

neuroscienceExtrahypothalamic GABAergic nociceptin–expressing neurons regulate AgRP neuron activity to control feeding behaviorMark A. Smith, Agharul I. Choudhury, Justyna A. Glegola, Paulius Viskaitis, Elaine E. Irvine, Pedro Caldas Custodio de Campos Silva, Sanjay Khadayate, Hanns Ulrich Zeilhofer, and Dominic J. Withers http://jci.me/130340

Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injuryWenjing Sun, Molly J.E. Larson, Conrad M. Kiyoshi, Alexander J. Annett, William A. Stalker, Juan Peng, and Andrea Tedeschi http://jci.me/130391

Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleusSeong Su Kang, Xia Liu, Eun Hee Ahn, Jie Xiang, Fredric P. Manfredsson, Xifei Yang, Hongbo R. Luo, L. Cameron Liles, David Weinshenker, and Keqiang Ye http://jci.me/130513

Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunityCatriona A. Wagner, Pamela J. Roqué, Trevor R. Mileur, Denny Liggitt, and Joan M. Goverman http://jci.me/132531

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oncologyDeregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneityTyler Risom, Xiaoyan Wang, Juan Liang, Xiaoli Zhang, Carl Pelz, Lydia G. Campbell, Jenny Eng, Koei Chin, Caroline Farrington, Goutham Narla, Ellen M. Langer, Xiao-Xin Sun, Yulong Su, Colin J. Daniel, Mu-Shui Dai, Christiane V. Löhr, and Rosalie C. Sears http://jci.me/126390

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activationKoji Haratani, Kimio Yonesaka, Shiki Takamura, Osamu Maenishi, Ryoji Kato, Naoki Takegawa, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi, Masayuki Takeda, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Junji Tsurutani, Kazuto Nishio, Katsumi Doi, Masaaki Miyazawa, and Kazuhiko Nakagawa http://jci.me/126598

Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapyCatherine E. Willoughby, Yanyan Jiang, Huw D. Thomas, Elaine Willmore, Suzanne Kyle, Anita Wittner, Nicole Phillips, Yan Zhao, Susan J. Tudhope, Lisa Prendergast, Gesa Junge, Luiza Madia Lourenco, M. Raymond V. Finlay, Paul Turner, Joanne M. Munck, Roger J. Griffin, Tommy Rennison, James Pickles, Celine Cano, David R. Newell, Helen L. Reeves, Anderson J. Ryan, and Stephen R. Wedge http://jci.me/127483

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy p. 3Nikita S. Sharma, Vineet K. Gupta, Vanessa T. Garrido, Roey Hadad, Brittany C. Durden, Kousik Kesh, Bhuwan Giri, Anthony Ferrantella, Vikas Dudeja, Ashok Saluja, and Sulagna Banerjee http://jci.me/127515

Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancerChanghao Chen, Yuming Luo, Wang He, Yue Zhao, Yao Kong, Hongwei Liu, Guangzheng Zhong, Yuting Li, Jun Li, Jian Huang, Rufu Chen, and Tianxin Lin http://jci.me/130892

ophthalmologyDominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy p. 3Camille Piro-Mégy, Emmanuelle Sarzi, Aleix Tarrés-Solé, Marie Péquignot, Fenna Hensen, Mélanie Quilès, Gaël Manes, Arka Chakraborty, Audrey Sénéchal, Béatrice Bocquet, Chantal Cazevieille, Agathe Roubertie, Agnès Müller, Majida Charif, David Goudenège, Guy Lenaers, Helmut Wilhelm, Ulrich Kellner, Nicole Weisschuh, Bernd Wissinger, Xavier Zanlonghi, Christian Hamel, Johannes N. Spelbrink, Maria Sola, and Cécile Delettre http://jci.me/128513

SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder p. 3Valentina Del Dotto, Farid Ullah, Ivano Di Meo, Pamela Magini, Mirjana Gusic, Alessandra Maresca, Leonardo Caporali, Flavia Palombo, Francesca Tagliavini, Evan Harris Baugh, Bertil Macao, Zsolt Szilagyi, Camille Peron, Margaret A. Gustafson, Kamal Khan, Chiara La Morgia, Piero Barboni, Michele Carbonelli, Maria Lucia Valentino, Rocco Liguori, Vandana Shashi, Jennifer Sullivan, Shashi Nagaraj, Mays El-Dairi, Alessandro Iannaccone, Ioana Cutcutache, Enrico Bertini, Rosalba Carrozzo, Francesco Emma, Francesca Diomedi-Camassei, Claudia Zanna, Martin Armstrong, Matthew Page, Nicholas Stong, Sylvia Boesch, Robert Kopajtich, Saskia Wortmann, Wolfgang Sperl, Erica E. Davis, William C. Copeland, Marco Seri, Maria Falkenberg, Holger Prokisch, Nicholas Katsanis, Valeria Tiranti, Tommaso Pippucci, and Valerio Carelli http://jci.me/128514

transplantationCross-dressed dendritic cells sustain effector T cell responses in islet and kidney allograftsAndrew D. Hughes, Daqiang Zhao, Hehua Dai, Khodor I. Abou-Daya, Roger Tieu, Rayan Rammal, Amanda L. Williams, Douglas P. Landsittel, Warren D. Shlomchik, Adrian E. Morelli, Martin H. Oberbarnscheidt, and Fadi G. Lakkis (ASCI) http://jci.me/125773

vascular biologySmooth muscle cell–specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasiaManish Jain, Nirav Dhanesha, Prakash Doddapattar, Mehul R. Chorawala, Manasa K. Nayak, Anne Cornelissen, Liang Guo, Aloke V. Finn, Steven R. Lentz, and Anil K. Chauhan http://jci.me/124708

Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injuryAndrew G. Masoud, Jiaxin Lin, Abul K. Azad, Maikel A. Farhan, Conrad Fischer, Lin F. Zhu, Hao Zhang, Banu Sis, Zamaneh Kassiri, Ronald B. Moore, Daniel Kim, Colin C. Anderson, John C. Vederas, Benjamin A. Adam, Gavin Y. Oudit, and Allan G. Murray http://jci.me/128469

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For JCI InsightEditorKathleen CollinsDeputy EditorsAndrew Lieberman, Donna Martin, Pavan ReddyAssociate EditorsSharlene M. Day, Gregory R. Dressler, David A. Fox, Santhi Ganesh, John Y. Kao, Celina G. Kleer, Carey Lumeng, Lona Mody, Bethany B. Moore, Alexey Nesvizhskii, Marina Pasca di Magliano, Subramaniam Pennathur, Darleen Sandoval, Andrew Tai, Weiping ZouExecutive EditorSarah C. JacksonSenior Science EditorCorinne Williams

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This MonthJanuary 2020

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Submit your work toJCI Insight today.

For JCI Insight online: jci.me/insight/4/23jci.me/insight/4/24

Pavan Reddy, MD, Deputy Editor, is the Frances and Victor Ginsberg Professor of Hematology/Oncology, Professor of Medicine and Pediatrics, Chief of the Division of Hematology/Oncology, and Dep-uty Director of the Comprehensive Cancer Center at the University of Michigan. His research is focused on improving outcomes after allogeneic hematopoietic cell transplantation, with the aims of discovering and translating novel immune modula-tors; and elucidating fundamental aspects of immune responses of T cells, dendritic cells, and target tis-

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Publication highlights Sun Y, Oravecz-Wilson K, Bridges S, McEachin R, Wu J, Kim SH, Taylor A, Zajac C, Fujiwara H, Peltier DC, Saunders T, Reddy P. miR-142 controls metabolic reprogram-ming that regulates dendritic cell activation. J Clin Invest. 2019;129(5):2029–2042.

Toubai T, Fujiwara H, Rossi C, Riwes M, Tamaki H, Zajac C, Liu C, Mathew AV, Byun J, Oravecz-Wilson K, Matsuda I, Sun Y, Peltier D, Wu J, Chen J, Seregin S, Henig I, Kim S, Brabbs S, Pennathur S, Chen G, Reddy P. Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial composition. Nat Microbiol. 2019;4(5):800–812.

Mathewson N, Jenq R, Mathew AV, Koenigsknecht M, Hanash A, Toubai T, Oravecz-Wilson K, Wu SR, Sun Y, Rossi C, Fujiwara H, Byun J, Shono Y, Lindemans C, Calafiore M, Schmidt TC, Honda K, Young VB, Pennathur S, Brink MVD, Reddy P. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol. 2016;17(5):505–513.

JCI Insight’s Editorial Board is composed of peer scientists at the University of Michigan and the University of Pennsylvania. Members of the Editorial Board review and oversee the peer review process of manuscripts directly submitted to JCI Insight, evaluate all transferred manuscripts, and meet weekly to discuss manuscripts under review.

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Editor’s picks

on the jci insight cover endocrinology

The choroid plexus secretes insulin in response to serotoninInsulin signaling in the brain has been implicated in cognition and disease; however, it is not clear whether insulin is generated in the brain or transported via the circulation. Caio Mazucanti and colleagues have shown that the choroid plexus (ChP) — a highly vascularized tissue within the brain ventricles that produces cerebrospinal fluid (CSF) and serves as the blood-CSF barrier (BCSFB) — produces and releases insulin. Epithelial cells of the ChP were the main source of insulin. While insulin release by ChP epithelial cells is calcium sensitive, it is not regulated by glucose. Instead, ChP-dependent insulin generation and release are mediated by serotonin via activation of the 5HT2C receptor. Moreover, depletion of serotonin in the brain of mice reduced insulin expression. Together, these results reveal the ChP as a source of insulin in the brain. The cover image shows C-peptide production (green) in primary ChP epithelial cells. Tight junctions (red, ZO-1) and nuclei (blue, DAPI) are also shown.

Release of insulin produced by the choroid plexis is regulated by serotonergic signalingCaio Henrique Mazucanti, Qing-Rong Liu, Doyle Lang, Nicholas Huang, Jennifer F. O’Connell, Simonetta Camandola, and Josephine M. Egan http://jci.me/131682

Immune checkpoint inhibitor resistancelinked to neutrophil contentImmune checkpoint inhibitor (ICI) therapy is a first line of defense for non–small cell lung cancer (NSCLC); however, many patients are refractory or develop resistance after initial response. Julia Kargl, Xiaodong Zhu, Huajia Zhang, and colleagues characterized cell populations and gene expression in NSCLC tumors and surrounding tissue, and they determined that tumors with an active immune response are characterized by high levels of CD8+ T cells and genes associated with T cell recruitment and activation. An abundance of myeloid cells, particularly neutrophils, and myeloid lineage–associated genes, coincided with a lack of CD4+ and CD8+ T cells. The ratio of CD8+ T cells to neutrophils within the tumor readily distinguished active and myeloid tumors and was predictive of patient response. In murine models, a combination of ICI with neutrophil antagonism promoted T cell infiltration of the tumor and

induction of IFN-γ–responsive genes. These results not only identify a myeloid signature associated with ICI resistance, but also support further investigation of neutrophil antagonism to enhance ICI in NSCLC.

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLCJulia Kargl, Xiaodong Zhu, Huajia Zhang, Grace H.Y. Yang, Travis J. Friesen, Melissa Shipley, Dean Y. Maeda, John A. Zebala, Jill McKay-Fleisch, Gavin Meredith, Afshin Mashadi-Hossein, Christina Baik, Robert H. Pierce, Mary W. Redman, Jeffrey C. Thompson, Steven M. Albelda, Hamid Bolouri, and A. McGarry Houghton http://jci.me/130850

immunology

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JCI Insight | Editor’s picks

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clinical trials pulmonology

Early trial of IL-7A–targeting antibody shows promise for type 1 diabetesType 1 diabetes (T1D) is characterized by immune-mediated loss of insulin-producing β cells. In murine models, IL-7 has been shown to promote diabetogenic T cell activity, and blocking IL-7 receptor α (IL-7RA) prevents and reverses diabetes in preclinical models. Kevan Herold and colleagues character-ized the response to a humanized IL-7RA antibody (RN168) in 37 patients with T1D as part of an early-phase, dose-ascending clinical trial. RN168 reduced populations of CD8+ and CD4+ effector and central memory T cells (Tefs and Tcms, respectively) and naive CD4+ T cells, along with expression of genes associated with T cell activation, survival, and differentiation. Moreover, RN168 enhanced the ratio of Tregs to CD8+ and CD4+ Tefs and Tcms. In general, RN168 was well tolerated; however, 2 patients exhibited reactivation of Epstein-Barr virus. Overall, the favorable immunomodulatory effects observed in this initial trial support further clinical investigation of RN168 for T1D.

Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in subjects with type 1 diabetesKevan C. Herold, Samantha L. Bucktrout, Xiao Wang, Bruce W. Bode, Stephen E. Gitelman, Peter A. Gottlieb, Jing Hughes, Tenshang Joh, Janet B. McGill, Jeremy H. Pettus, Shobha Potluri, Desmond Schatz, Megan Shannon, Chandrasekhar Udata, Gilbert Wong, Matteo Levisetti, Bishu J. Ganguly, Pamela D. Garzone, and the RN168 Working Group http://jci.me/126054

L-Citrulline improves asthma control in obese subjectsObesity exacerbates preexisting asthma and is linked to late-onset asthma, particularly in females. Moreover, obese individuals with asthma often exhibit a reduced response to inhaled corticosteroids. Obesity-associated metabolic changes in the lung include a reduction of L-arginine levels and higher concentrations of asymmetric methyl arginine (ADMA), which favors epithelial inducible NO synthase (iNOS) uncoupling, thereby promoting formation of ROS over NO production. L-Citrulline prevents iNOS uncoupling in cultured airway epithelial cells from obese asthma patients but has not yet been tested in patients. Fernando Holguin, Loretta Que, and colleagues performed a pilot study examining the effect of L-citrulline in a small cohort of obese patients with poorly controlled asthma and found that short-term administration of L-citrulline improved asthma control and increased exhaled NO levels. In particular, obese females with late-onset asthma exhibited the greatest benefit from L-citrulline therapy, supporting further clinical evaluation of L-citrulline for improving asthma control.

L-Citrulline increases nitric oxide and improves control in obese asthmaticsFernando Holguin, Hartmut Grasemann, Sunita Sharma, Daniel Winnica, Karen Wasil, Vong Smith, Margaret H. Cruse, Nancy Perez, Erika Coleman, Timothy J. Scialla, and Loretta G. Que http://jci.me/131733

hepatology

Fecal transfer–induced functional microbial changes improve hepatic encephalopathyHepatic encephalopathy (HE) is a complication of cirrhosis that affects patients clinically and psychosocially. Reprogramming of the gut microbiota with laxatives and antibiotics can reduce HE symptoms, but these may not be enough. Fecal microbial transplant (FMT) could help, but resultant microbial functional changes are unclear. Jasmohan Bajaj and colleagues conducted a small placebo-controlled randomized trial to evaluate the effect of oral capsular FMT in HE to determine the microbial functional fingerprint of subject response. Stool microbiota and bile acid (BA) composition and serum IL-6, BA, and LPS-binding protein (LBP) levels were measured along with EncephalApp analysis of cognitive function. Overall, FMT, but not placebo, reduced serum IL-6 and LBP, increased secondary BA formation, and improved EncephalApp performance. Beneficial bacterial taxa, including Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, most strongly associated with reduced inflammation and cognitive improvement. Moreover, secondary BA changes differentiated between FMT recipients responders and nonresponders. These results support further investigation of FMT for HE.

Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosisJasmohan S. Bajaj (ASCI), Nita Salzman, Chathur Acharya, Hajime Takei, Genta Kakiyama, Andrew Fagan, Melanie B. White, Edith A. Gavis, Mary L. Holtz, Michael Hayward, Hiroshi Nittono, Phillip B. Hylemon, I. Jane Cox, Roger Williams, Simon D. Taylor-Robinson, Richard K. Sterling, Scott C. Matherly, Michael Fuchs, Hannah Lee, Puneet Puri, R. Todd Stravitz, Arun J. Sanyal, Lola Ajayi, Adrien Le Guennec, R. Andrew Atkinson, Mohammad S. Siddiqui, Velimir Luketic, William M. Pandak, Masoumeh Sikaroodi, and Patrick M. Gillevet http://jci.me/133410

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JCI Insight | Editor’s picks

gastroenterology

infectious disease

Canonical viral-recognizing TLR promotes bacterial growth in the lung

Gut-resident γδ T cell population exhibits potent antitumor activityWithin the human intestinal epithelium, γδ T cells represent a substantial portion of intraepithelial lymphocytes (IELs). Neither the origin nor function of these tissue-resident cells is fully understood. Joanna Mikulak, Ferdinando Oriolo, and colleagues purified γδ T cells from healthy individuals and CRC patients, and they identified a population characterized by the expression of NKp46 that constitutes the largest fraction of gut-resident IELs (see accompanying image). The ontogeny and tropism of NKp46+/Vδ1 IELs was dependent on both distinctive features of Vδ1 thymic precursors and gut-environmental factors. NKp46 expression promoted antitumor functions, and a higher frequency of these cells in colorectal cancer (CRC) patients correlated with a reduced risk of metastatic disease. The CRC tumor microenvironment was shown to prevent expansion of NKp46+ γδ T cells in vitro, a result that supports the overall low frequencies of these cells in CRC tumors.

NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancerJoanna Mikulak, Ferdinando Oriolo, Elena Bruni, Alessandra Roberto, Federico S. Colombo, Anna Villa, Marita Bosticardo, Ileana Bortolomai, Elena Lo Presti, Serena Meraviglia, Francesco Dieli, Stefania Vetrano, Silvio Danese, Silvia Della Bella, Michele M. Carvello, Matteo Sacchi, Giovanni Cugini, Giovanni Colombo, Marco Klinger, Paola Spaggiari, Massimo Roncalli, Immo Prinz, Sarina Ravens, Biagio di Lorenzo, Emanuela Marcenaro, Bruno Silva-Santos, Antonino Spinelli, and Domenico Mavilio http://jci.me/125884

Pathogen recognition receptors (PRRs) play integral roles in pathogen detection and clearance. Canonical-ly, TLR3 is considered a viral-recognizing PRR; however, recent studies support a role for TLR3 in the initiation of the inflammatory response following blunt trauma–induced lung contusion. Using murine models of Klebsiella pneumoniae (KP), Madathil-parambil Suresh and colleagues demonstrated that TLR3-deficient mice were protected from lethal KP pneumonia challenge, and that this protection was mediated by increased bactericidal and phagocytic

activity of TLR3-deficient alveolar macrophages and an increase in neutrophil infiltration in the lung (see the accompanying image). Moreover, pharmacological inhibition of TLR3/dsRNA complex formation or adoptive transfer of TLR3-deficient alveolar macrophages protected WT mice from KP pneumonia. Finally, TLR3 expression was increased in postmortem lungs of patients with KP and other Gram-negative bacterial pneumonia. Together, these results represent a paradigm shift in understanding the mechanistic role of TLR3 in bacterial pneumonia.

TLR3 absence confers increased survival with improved macrophage activity against pneumoniaMadathilparambil V. Suresh, Vladislav A. Dolgachev, Boya Zhang, Sanjay Balijepalli, Samantha Swamy, Jashitha Mooliyil, Georgia Kralovich, Bivin Thomas, David Machado-Aranda, Monita Karmakar, Sanjeev Lalwani, Arulselvi Subramanian, Arun Anantharam, Bethany B. Moore, and Krishnan Raghavendran http://jci.me/131195

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Current articlesA composite immune signature parallels disease progression across T1D subjectsCate Speake, Samuel O. Skinner, Dror Berel, Elizabeth Whalen, Matthew J. Dufort, William Chad Young, Jared M. Odegard, Anne M. Pesenacker, Frans K. Gorus, Eddie A. James, Megan K. Levings, Peter S. Linsley, Eitan M. Akirav, Alberto Pugliese, Martin J. Hessner, Gerald T. Nepom, Raphael Gottardo, and S. Alice Long http://jci.me/126917

Osteoprotective action of low-salt diet requires myeloid cell–derived NFAT5Agnes Schröder, Patrick Neubert, Jens Titze, Aline Bozec, Wolfgang Neuhofer, Peter Proff, Christian Kirschneck, and Jonathan Jantsch http://jci.me/127868

Proteasome inhibition preserves longitudinal growth of denervated muscle and prevents neonatal neuromuscular contracturesSia Nikolaou, Alyssa A.W. Cramer, Liangjun Hu, Qingnian Goh, Douglas P. Millay, and Roger Cornwall http://jci.me/128454

Mevastatin promotes healing by targeting caveolin-1 to restore EGFR signalingAndrew P. Sawaya, Ivan Jozic, Rivka C. Stone, Irena Pastar, Andjela N. Egger, Olivera Stojadinovic, George D. Glinos, Robert S. Kirsner, and Marjana Tomic-Canic http://jci.me/129320

Uncoupled turnover disrupts mitochondrial quality control in diabetic retinopathyJose R. Hombrebueno, Lauren Cairns, Louise R. Dutton, Timothy J. Lyons, Derek P. Brazil, Paul Moynagh, Tim M. Curtis, and Heping Xu http://jci.me/129760

Cytomegalovirus infection is a risk factor for tuberculosis disease in infantsJulius Müller, Rachel Tanner, Magali Matsumiya, Margaret A. Snowden, Bernard Landry, Iman Satti, Stephanie A. Harris, Matthew K. O’Shea, Lisa Stockdale, Leanne Marsay, Agnieszka Chomka, Rachel Harrington-Kandt, Zita-Rose Manjaly Thomas, Vivek Naranbhai, Elena Stylianou, Stanley Kimbung Mbandi, Mark Hatherill, Gregory Hussey, Hassan Mahomed, Michele Tameris, J. Bruce McClain, Thomas G. Evans, Willem A. Hanekom, Thomas J. Scriba, Helen McShane, and Helen A. Fletcher http://jci.me/130090

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization patternAlexander Teumer, Teresa Trenkwalder, Thorsten Kessler, Yalda Jamshidi, Marten E. van den Berg, Bernhard Kaess, Christopher P. Nelson, Rachel Bastiaenen, Marzia De Bortoli, Alessandra Rossini, Isabel Deisenhofer, Klaus Stark, Solmaz Assa, Peter S. Braund, Claudia Cabrera, Anna F. Dominiczak, Martin Gögele, Leanne M. Hall, M. Arfan Ikram, Maryam Kavousi, Karl J. Lackner, Lifelines Cohort Study, Christian Müller, Thomas Münzel, Matthias Nauck, Sandosh Padmanabhan, Norbert Pfeiffer, Tim D. Spector, Andre G. Uitterlinden, Niek Verweij, Uwe Völker, Helen R. Warren, Mobeen Zafar, Stephan B. Felix, Jan A. Kors, Harold Snieder, Patricia B. Munroe, Cristian Pattaro, Christian Fuchsberger, Georg Schmidt, Ilja M. Nolte, Heribert Schunkert, Peter P. Pramstaller, Philipp S. Wild, Pim van der Harst, Bruno H. Stricker, Renate B. Schnabel, Nilesh J. Samani, Christian Hengstenberg, Marcus Dörr, Elijah R. Behr, and Wibke Reinhard http://jci.me/131156

TLR3 absence confers increased survival with improved macrophage activity against pneumonia p. 13Madathilparambil V. Suresh, Vladislov A. Dolgachev, Boya Zhang, Sanjay Balijepalli, Samantha Swamy, Jashitha Mooliyil, Georgia Kralovich, Bivin Thomas, David Machado-Aranda, Monita Karmakar, Sanjeev Lalwani, Arulselvi Subramanian, Arun Anantharam, Bethany B. Moore, and Krishnan Raghavendran http://jci.me/131195

ER stress and Rho kinase activation underlie the vasculopathy of CADASILKarla B. Neves, Adam P. Harvey, Fiona Moreton, Augusto C. Montezano, Francisco J. Rios, Rhéure Alves-Lopes, Aurelie Nguyen Dinh Cat, Paul Rocchicciolli, Christian Delles, Anne Joutel, Keith Muir, and Rhian M. Touyz http://jci.me/131344

A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemiaMianmian Yin, Timour Baslan, Robert L. Walker, Yuelin J. Zhu, Amy Freeland, Toshihiro Matsukawa, Sriram Sridharan, André Nussenzweig, Steven C. Pruitt, Scott W. Lowe, Paul S. Meltzer, and Peter D. Aplan http://jci.me/131434

Neutrophil-targeted, protease-activated pulmonary drug delivery blocks airway and systemic inflammationJoscelyn C. Mejías, Osric A. Forrest, Camilla Margaroli, David A. Frey Rubio, Liliana Viera, Jindong Li, Xin Xu, Amit Gaggar, Rabindra Tirouvanziam, and Krishnendu Roy http://jci.me/131468

Cardiac sympathectomy and spinal cord stimulation attenuate reflex-mediated norepinephrine release during ischemia preventing ventricular fibrillationJeffrey L. Ardell, Robert D. Foreman, J. Andrew Armour, and Kalyanam Shivkumar (ASCI) http://jci.me/131648

Release of insulin produced by the choroid plexis is regulated by serotonergic signaling p. 11Caio Henrique Mazucanti, Qing-Rong Liu, Doyle Lang, Nicholas Huang, Jennifer F. O’Connell, Simonetta Camandola, Josephine M. Egan http://jci.me/131682

C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infectionsSerena Bettoni, Jutamas Shaughnessy, Karolina Maziarz, David Ermert, Sunita Gulati, Bo Zheng, Matthias Mörgelin, Susanne Jacobsson, Kristian Riesbeck, Magnus Unemo Sanjay Ram (ASCI), and Anna M. Blom http://jci.me/131886

MEK1 regulates pulmonary macrophage inflammatory responses and resolution of acute lung injuryMatthew E. Long, Ke-Qin Gong, William E. Eddy, Joseph S. Volk, Eric D. Morrell, Carmen Mikacenic, T. Eoin West, Shawn J. Skerrett, Jean Charron, W. Conrad Liles, and Anne M. Manicone http://jci.me/132377

EPHB2 carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signalingShinya Sato, Suhas Vasaikar, Adel Eskaros, Young Kim, James S. Lewis, Bing Zhang, Andries Zijlstra, and Alissa M. Weaver http://jci.me/132447

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Current articles

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse modelZhousheng Xiao, Gwendalyn King, Salvatore Mancarella, Undral Munkhsaikhan, Li Cao, Chun Cai, and Leigh Darryl Quarles (ASCI) http://jci.me/132820

Mitophagy-dependent macrophage reprogramming protects against kidney fibrosisDivya Bhatia, Kuei-Pin Chung, Kiichi Nakahira, Edwin Patino, Michelle C. Rice, Lisa K. Torres, Thangamani Muthukumar, Augustine M.K. Choi, Oleh M. Akchurin, and Mary E. Choi (ASCI) http://jci.me/132826

Discovery of specialized NK cell populations infiltrating human melanoma metastasesLucas Ferrari de Andrade, Yuheng Lu, Adrienne Luoma, Yoshinaga Ito, Deng Pan, Jason W. Pyrdol, Charles H. Yoon, Guo-Cheng Yuan, and Kai W. Wucherpfennig (ASCI) http://jci.me/133103

Tubular injury triggers podocyte dysfunction by β-catenin–driven release of MMP-7Roderick J. Tan, Yingjian Li, Brittney M. Rush, Débora Malta Cerqueira, Dong Zhou, Haiyan Fu, Jacqueline Ho, Donna Beer Stolz, and Youhua Liu http://jci.me/122399

Non–fibro-adipogenic pericytes from human embryonic stem cells attenuate degeneration of the chronically injured mouse muscleGina M. Mosich, Regina Husman, Paras Shah, Abhinav Sharma, Kevin Ressadeh, Temidayo Aderibigbe, Vivian J. Hu, Daniel J. McClintick, Genbin Wu, Jonathan D. Gatto, Haibin Xi, April D. Pyle, Bruno Péault, Frank A. Petrigliano, and Ayelet Dar http://jci.me/125334

Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes p. 12Kevan C. Herold, Samantha L. Bucktrout, Xiao Wang, Bruce W. Bode, Stephen E. Gitelman, Peter A. Gottlieb, Jing Hughes, Tenshang Joh, Janet B. McGill, Jeremy H. Pettus, Shobha Potluri, Desmond Schatz, Megan Shannon, Chandrasekhar Udata, Gilbert Wong, Matteo Levisetti, Bishu J. Ganguly, Pamela D. Garzone, and the RN168 Working Group http://jci.me/126054

Center for Neural Science and Medicine – Faculty Outstanding opportunities for faculty scientists at the assistant, associate and professor level exist in our new Center for Neural Science and Medicine (CNSM) at Cedars-Sinai Medical Center. Under the direction of Dr. Robert Baloh, MD, PhD, the Center brings together neuroscientists from across a range of departments and disciplines to facilitate collaborative efforts to improve our understanding of the nervous system. https://www.cedars-sinai.edu/Research/Research-Areas/Neural-Science-and-Medicine-Center/.

The mission of the newly formed CNSM is to define fundamental principles that underlie nervous system function in health and disease, and to harness those principles to develop transformative treatments for nervous system disorders. Specific focus areas include: Neural Injury, Degeneration and Neuroimmunology; Cognitive and Systems Neuroscience; Neurodevelopment and Neuroregeneration. Successful candidates are expected to develop a cutting-edge independent research program. We are deeply dedicated to maintaining a diverse and vibrant group of faculty interested in collaborating across boundaries to challenge dogma and drive paradigm change.

In addition to recruiting high quality basic and physician scientists to leverage existing areas of strength in the neuroscience at Cedars- Sinai, the CNSM supports seed funding to enhance collaborative neuroscience efforts across campus, oversees neuroscience education for the Cedars-Sinai PhD program, a monthly seminar series and a yearly symposium in neuroscience. The Center’s mission is achieved in partnership with Neurology, Neurosurgery, Medicine, Pathology, Imaging, Biomedical Sciences and the Board of Governors Regenerative Medicine Institute, and recruits will have joint appointments in one or more of these departments.

Candidates will have the following qualifications:

• Doctorate degree (PhD, MD, or joint MD, PhD) • Strong commitment to research with a track record of peer reviewed publications • For Associate or Full Professor consideration, experience as a principal investigator with an active externally

funded research program and a strong publication record

Cedars-Sinai Health System is among the nation’s leading providers of healthcare services, medical education and medical research, with total annual revenues of $3.3 billion, and is one of the largest non-profit academic medical centers in the U.S. In addition to a large research enterprise, comprising more than 1,500 research projects and a robust technology transfer portfolio, as well as highly sought-after training programs, including more than 400 medical residents and fellows, Cedars- Sinai is widely known for its national leadership in transforming healthcare for the benefit of patients. Cedars-Sinai is a teaching hospital for a variety of regional training programs including the Cedars-Sinai MS and PhD programs, and UCLA.

Qualified applicants can send a cover letter, CV and description of proposed research to:

academic.recruiting@cshs.org We are an equal opportunity/affirmative action employer M/F/Vets/Disabled

A D V E R T I S E M E N T

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NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer p. 13Joanna Mikulak, Ferdinando Oriolo, Elena Bruni, Alessandra Roberto, Federico S. Colombo, Anna Villa, Marita Bosticardo, Ileana Bortolomai, Elena Lo Presti, Serena Meraviglia, Francesco Dieli, Stefania Vetrano, Silvio Danese, Silvia Della Bella, Michele M. Carvello, Matteo Sacchi, Giovanni Cugini, Giovanni Colombo, Marco Klinger, Paola Spaggiari, Massimo Roncalli, Immo Prinz, Sarina Ravens, Biagio di Lorenzo, Emanuela Marcenaro, Bruno Silva-Santos, Antonino Spinelli, and Domenico Mavilio http://jci.me/125884

Targeting liver stage malaria with metforminIset Medina Vera, Margarida T. Grilo Ruivo, Leonardo F. Lemos Rocha, Sofia Marques, Sangeeta N. Bhatia, Maria M. Mota, and Liliana Mancio-Silva http://jci.me/127441

Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancerYa Zhang, Xuefeng Wu, Yan Kai, Chia-Han Lee, Fengdong Cheng, Yixuan Li, Yongbao Zhuang, Javid Ghaemmaghami, Kun-Han Chuang, Zhuo Liu, Yunxiao Meng, Meghana Keswani, Nancy R. Gough, Xiaojun Wu, Wenge Zhu, Alexandros Tzatsos, Weiqun Peng, Edward Seto, Eduardo M. Sotomayor, and Xiaoyan Zheng http://jci.me/129334

Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissuesMargaret M. Lowe, Ian Boothby, Sean Clancy, Richard S. Ahn, Wilson Liao, David N. Nguyen, Kathrin Schumann, Alexander Marson, Kelly M. Mahuron, Gillian A. Kingsbury, Zheng Liu, Priscila Munoz Sandoval, Robert Sanchez Rodriguez, Mariela L. Pauli, Keyon Taravati, Sarah T. Arron, Isaac M. Neuhaus, Hobart W. Harris, Esther A. Kim, Uk Sok Shin, Matthew F. Krummel, Adil Daud, Tiffany C. Scharschmidt, and Michael D. Rosenblum http://jci.me/129756

Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosisChristopher D. Wiley, Alexis N. Brumwell, Sonnet S. Davis, Julia R. Jackson, Alexis Valdovinos, Cheresa Calhoun, Fatouma Alimirah, Carlos A. Castellanos, Richard Ruan, Ying Wei, Harold A. Chapman, Arvind Ramanathan, Judith Campisi, and Claude Jourdan Le Saux http://jci.me/130056

S-nitrosylation of connexin43 hemichannels elicits cardiac stress–induced arrhythmias in Duchenne muscular dystrophy miceMauricio A. Lillo, Eric Himelman, Natalia Shirokova, Lai-Hua Xie, Diego Fraidenraich, and Jorge E. Contreras http://jci.me/130091

BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA– Indian adultsSrabanti Rakshit, Asma Ahmed, Vasista Adiga, Bharath K. Sundararaj, Pravat Nalini Sahoo, John Kenneth, George D’Souza, Wesley Bonam, Christina Johnson, Kees L.M.C. Franken, Tom H.M. Ottenhoff, Greg Finak, Raphael Gottardo, Kenneth D. Stuart, Stephen C. De Rosa, M. Juliana McElrath, and Annapurna Vyakarnam http://jci.me/130540

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC p. 11Julia Kargl, Xiaodong Zhu, Huajia Zhang, Grace H.Y. Yang, Travis J. Friesen, Melissa Shipley, Dean Y. Maeda, John A. Zebala, Jill McKay-Fleisch, Gavin Meredith, Afshin Mashadi-Hossein, Christina Baik, Robert H. Pierce, Mary W. Redman, Jeffrey C. Thompson, Steven M. Albelda, Hamid Bolouri, and A. McGarry Houghton (ASCI) http://jci.me/130850

Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanismHuashan Liu, Zhenxing Liang, Fengwei Wang, Chi Zhou, Xiaobin Zheng, Tuo Hu, Xiaowen He, Xianrui Wu, and Ping Lan http://jci.me/131273

L-Citrulline increases nitric oxide and improves control in obese asthmatics p. 12Fernando Holguin, Hartmut Grasemann, Sunita Sharma, Daniel Winnica, Karen Wasil, Vong Smith, Margaret H. Cruse, Nancy Perez, Erika Coleman, Timothy J. Scialla, and Loretta G. Que http://jci.me/131733

CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosisLi-Chung Tsao, Erika J. Crosby, Timothy N. Trotter, Pankaj Agarwal, Bin-Jin Hwang, Chaitanya Acharya, Casey W. Shuptrine, Tao Wang, Junping Wei, Xiao Yang, Gangjun Lei, Cong-Xiao Liu, Christopher A. Rabiola, Lewis A. Chodosh, William J. Muller, Herbert Kim Lyerly, and Zachary C. Hartman http://jci.me/131882

Low-level Cxcr4-haploinsufficient HSC engraftment is sufficient to correct leukopenia in WHIM syndrome miceJi-Liang Gao, Albert Owusu-Ansah, Andrea Paun, Kimberly Beacht, Erin Yim, Marie Siwicki, Alexander Yang, Qian Liu, David H. McDermott, and Philip M. Murphy (ASCI) http://jci.me/132140

Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogrammingMattia Quattrocelli, Aaron S. Zelikovich, Zhen Jiang, Clara Bien Peek, Alexis R. Demonbreun, Nancy L. Kuntz, Grant D. Barish, Saptarsi M. Haldar, Joseph Bass, and Elizabeth M. McNally (ASCI) http://jci.me/132402

TNFR2 limits proinflammatory astrocyte functions during EAE induced by pathogenic DR2b-restricted T cellsItay Raphael, Francisco Gomez-Rivera, Rebecca A. Raphael, Rachel R. Robinson, Saisha Nalawade, and Thomas G. Forsthuber http://jci.me/132527

Mitochondrial arginase-2 is a cell-autonomous regulator of CD8+ T cell function and antitumor efficacyAdrià-Arnau Martí Líndez, Isabelle Dunand-Sauthier, Mark Conti, Florian Gobet, Nicolás Núñez, J. Thomas Hannich, Howard Riezman, Roger Geiger, Alessandra Piersigilli, Kerstin Hahn, Sylvain Lemeille, Burkhard Becher, Thibaut De Smedt, Stéphanie Hugues, and Walter Reith http://jci.me/132975

Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis p. 12Jasmohan S. Bajaj (ASCI), Nita Salzman, Chathur Acharya, Hajime Takei, Genta Kakiyama, Andrew Fagan, Melanie B. White, Edith A. Gavis, Mary L. Holtz, Michael Hayward, Hiroshi Nittono, Phillip B. Hylemon, I. Jane Cox, Roger Williams, Simon D. Taylor-Robinson, Richard K. Sterling, Scott C. Matherly, Michael Fuchs, Hannah Lee, Puneet Puri, R. Todd Stravitz, Arun J. Sanyal, Lola Ajayi, Adrien Le Guennec, R. Andrew Atkinson, Mohammad S. Siddiqui, Velimir Luketic, William M. Pandak, Masoumeh Sikaroodi, and Patrick M. Gillevet http://jci.me/133410

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