jci.org/this-month

Platelets contribute to cystic fibrosis inflammation 3

Connecting connexin-43 to dystrophic cardiomyo-pathy 4

Deep tissue reservoirs for HIV 4

CoREST controls Treg contributions to antitumor immunity 5

Review Series: Immunotherapy in Hematological Cancers edited by Leo Luznik 6

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

Scan for the digital version of JCI This Month.

April 2020

This Month

IFN-drivenneuroinflammation in Alzheimer disease p. 2

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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 a p r i l 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

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Staff EditorsExecutive EditorSarah C. Jackson

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Editorial InternBouchra Taib

JCI This Month ISSN 2380-3029 (print)ISSN 2380-3037 (online)For the full JCI online: jci.me/130/4

This MonthApril 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.

The scientific community is grappling with the COVID-19 pandemic on several fronts. Some colleagues are working hard to under-stand the spread of the disease, provide supportive care, and develop thera-pies, while others are leading hospital responses to the demands of patients with diagnostic and intensive care needs. Unfortunately, many research institutions are facing shutdowns or restricted working conditions in other areas of research, as universities comply with regulations for “social distanc-ing” to prevent the spread of the virus.

While it is unknown how long this pause in noncritical research activities will last, it is likely to be several weeks or months. At the JCI and JCI Insight, our editorial boards are made up of active academic researchers, and we know firsthand how these disruptions are impacting our community. As editors, we always strive to be discerning about requests for revisions to manuscripts. We are now asking our editors and peer reviewers to be even more vigilant in guard-ing against unreasonable demands for revision. For exceptional manuscripts, we may overrule requests from reviewers that are beyond the scope of revision in this climate. In other cases, we may determine that additional studies are required to support fundamental conclusions. Under these circumstances, we want to ensure that authors have adequate time to add studies once laboratory activities resume. Our goal is not to compromise on the quality of work, but to recognize the enormous disruption posed by the COVID-19 pandemic. Science and discovery won’t be on a pause forever, but we will ensure a fair standard for our authors during these extraordinary times.

Rexford S. Ahima Editor In Chief, The Journal of Clinical Investigation

Sarah Jackson Executive Editor, The Journal of Clinical Investigation | JCI Insight

Arturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli Deputy Editors, The Journal of Clinical Investigation

Kathleen L. Collins Editor In Chief, JCI Insight

Andrew P. Lieberman, Donna M. Martin, Pavan Reddy Deputy Editors, JCI Insight

To read the complete editorial, visit http://jci.me/138305.

Changes to the editorial process during the COVID-19 pandemic

From the Editors

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research

Editor’s pickson the jci cover neuroscience

Amyloid-responsive interferon signaling provokes neuroinflammation in models of Alzheimer disease

Microbial metabolites mediate parathyroid hormone–driven bone formation in mice

In Alzheimer disease (AD), neurodegeneration is accompanied by chronic CNS inflammation, including reactive microglia and elevated levels of proinflammatory cytokines. Pathologic neuroinflammation in AD may be driven by immunogenic responses to β-amyloid (Aβ) fibrils, aggregates of soluble proteins that form insoluble secondary structures. In this issue of the JCI, Ethan Roy et al. demonstrate that type I interferon (IFN) signaling is activated in Aβ-driven mouse models of AD. Exposure to nucleic acid–containing amyloid fibrils also elicited IFN-associated cytokine expression in the brains of wild-type mice, suggesting that IFN signaling contributes to the immunogenic response to amyloid. In AD models, amyloid-driven neuroinflammation and complement C3–dependent loss of hippocampal synapses involved activation of IFN pathway genes in microglia. Blocking IFN signaling in these models reduced microgliosis and synapse loss, supporting the IFN pathway’s critical contribution to amyloid-driven neuropathology. Finally, the researchers reveal that upregulation of the IFN pathway in clinical AD correlates with disease sever-ity and complement activation in the CNS. The accompanying Commentary by Stefano Pluchino and Cory Willis highlights IFN targeting as a potential therapeutic strategy for AD. The cover image shows the accumulation of activated microglia (Iba1, green; Clec7a, yellow) in association with Aβ plaques (blue) in a mouse model of AD. Image credit: Ethan Roy.

Type I interferon response drives neuroinflammation and synapse loss in Alzheimer diseaseEthan R. Roy, Baiping Wang, Ying-wooi Wan, Gabriel Chiu, Allysa Cole, Zhuoran Yin, Nicholas E. Propson, Yin Xu, Joanna L. Jankowsky, Zhandong Liu, Virginia M.-Y. Lee, John Q. Trojanowski, Stephen D. Ginsberg, Oleg Butovsky, Hui Zheng, and Wei Cao http://jci.me/133737

Related CommentaryIntrinsic antiviral immunity drives neurodegeneration in Alzheimer diseaseStefano Pluchino and Cory Willis http://jci.me/135906

bone biology

The gut microbiome has emerged as a bone regulator in health and disease. One mechanism whereby the microbiome affects bone is via its production of short-chain fatty acids (SCFAs), microbial metabolites that regulate bone formation through their effects on immune cells. Jau-Yi Li and colleagues now reveal that the osteogenic effects of parathyroid hormone (PTH) require microbial SCFA production. Intermittent PTH treatment failed to stimulate bone formation in germ-free and antibiotic-treated female mice, but supplementing these mice with physiologic amounts of the SCFA butyrate restored PTH-induced increases in bone formation and bone mass. Butyrate was essential for PTH-induced Treg differentiation, which promoted bone formation by stimulating osteogenic Wnt10b production by CD8+ T cells. Sundeep Khosla’s accompanying Commentary discusses these mechanistic

insights, which shed light upon potential therapies for osteoporosis as well as key interactions between the microbiome and immune system.

Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiotaJau-Yi Li, Mingcan Yu, Subhashis Pal, Abdul Malik Tyagi, Hamid Dar, Jonathan Adams, M. Neale Weitzmann, Rheinallt M. Jones, and Roberto Pacifici (ASCI) http://jci.me/133473

Related CommentaryThe microbiome adds to the complexity of parathyroid hormone action on boneSundeep Khosla (ASCI) http://jci.me/135712

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JCI | Research: Editor’s picks

pulmonology

Platelets contribute to lung hyperinflammation in model of cystic fibrosisCystic fibrosis (CF) is caused by mutations in CFTR, encoding an epithelial chloride channel. While CF is typically associated with abnormal mucus secretions that affect lung and other tissues, inflammation plays a major role in disease progression. Following observations that hematopoietic cells may mediate inflammatory cytokine responses in CF models, Guadalupe Ortiz-Muñoz, Michelle Yu, and colleagues focused on the contribution of platelets to hyperinflam-mation. In mice, selectively deleting Cftr in platelets led to increased lung inflammation and platelet activation following intratracheal bacterial challenge. Hyperactivity in Cftr-deficient platelets was linked to increased calcium entry, and normalizing calcium flux protected against lung injury in a CF model. In the accompanying Commentary, Guy Zimmerman notes the study’s observation of blunted platelet activation in CF patients receiving CFTR-modulating treatments and suggests that ameliorating aberrant platelet function could be beneficial in CF.

Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammationGuadalupe Ortiz-Muñoz, Michelle A. Yu, Emma Lefrançais, Beñat Mallavia, Colin Valet, Jennifer J. Tian, Serena Ranucci, Kristin M. Wang, Zhe Liu, Nicholas Kwaan, Diana Dawson, Mary Ellen Kleinhenz, Fadi T. Khasawneh, Peter M. Haggie, Alan S. Verkman, and Mark R. Looney (ASCI) http://jci.me/129635

Related CommentaryPlatelets: inflammatory effector cells in the conflagration of cystic fibrosis lung diseaseGuy A. Zimmerman (ASCI) http://jci.me/135949

neuroscience

Profilin 1 coordinates cytoskeletal remodeling to support axonal regrowthThe adult CNS has a limited ability to regrow damaged axons, a process that requires coordinated remodeling of actin and microtubules and the formation of a competent axon growth cone. In this issue, Rita Pinto-Costa and colleagues identified the actin-binding protein profilin 1 (Pfn1) as a regulator of actin and microtubule dynamics that supports axonal regrowth and regeneration in mouse models of nerve injury. Peripheral nerve injury led to increased Pfn1 activity in growth cones, where it promoted cytoskeletal dynamics that enhanced axonal regeneration. Loss of Pfn1 impaired axonal growth in both peripheral and spinal cord injury as well as reducing axonal and dendritic growth in cultured hippocampal neurons. In mice, systemic delivery of active Pfn1 improved the regenerative capacity of peripheral axons following sciatic nerve injury (see the accompanying image), demonstrat-ing the potential of Pfn1-targeting therapies to enhance nerve regrowth and functional recovery after injury.

Profilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regenerationRita Pinto-Costa, Sara C. Sousa, Sérgio C. Leite, Joana Nogueira-Rodrigues, Tiago Ferreira da Silva, Diana Machado, Joana Marques, Ana Catarina Costa, Márcia A. Liz, Francesca Bartolini, Pedro Brites, Mercedes Costell, Reinhard Fässler, and Mónica M. Sousa http://jci.me/125771

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JCI | Research: Editor’s picks

Targeting connexin-43 cardiac remodeling prevents heart dysfunction in dystrophic miceTherapeutic advancements combating skeletal muscle and respiratory dysfunction in Duchenne muscular dystrophy (DMD) have prolonged patient lives, making cardiomyopathy the leading cause of death for DMD patients. While aberrant remodeling of connexin-43 is associated with DMD cardiomy-opathy, its mechanistic role remains unclear. Eric Himelman and colleagues reveal that cardiac connexin-43 is hypophosphorylated at a triplet of serine sites in human DMD as well as in the mdx mouse model and hypothesized that this modification triggers connexin-43 remodeling. To test this, phosphomimetic mutations of the Cx43 serine-triplet were made in mdx mice. These mice were protected against cardiomyopathy and stress-related lethality by the prevention of connexin-43 remodeling (compare mdx heart [left] with mdx heart expressing the connexin-43 phosphomimetic [right]). In the accompanying Commentary, Robin Shaw and Jeffrey Saffitz suggest that therapies targeting connexin-43 may be capable of preventing cardiac dysfunction in DMD patients.

Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathyEric Himelman, Mauricio A. Lillo, Julie Nouet, J. Patrick Gonzalez, Qingshi Zhao, Lai-Hua Xie, Hong Li, Tong Liu, Xander H.T. Wehrens, Paul D. Lampe, Glenn I. Fishman, Natalia Shirokova, Jorge E. Contreras, and Diego Fraidenraich http://jci.me/128190

Related CommentaryA role for connexin-43 in Duchenne muscular dystrophy cardiomyopathy

Robin M. Shaw and Jeffrey E. Saffitz http://jci.me/135007

Characterizing HIV’s deep tissue reservoirsAlthough antiretroviral therapy (ART) has dramati-cally improved the life expectancy of HIV-infected individuals, HIV remains incurable because of the persistence of the virus in latent reservoirs. Many tissue reservoirs remain relatively uncharacterized due to the inability to sample from these regions in patients. Antoine Chaillon, Sara Gianella, and colleagues evaluated HIV reservoirs in 6 ART-treated individuals with HIV who donated their bodies for rapid autopsy after death through the Last Gift program, assessing HIV DNA levels in blood as well as in samples collected from 26 tissue sites postmortem. HIV was detected in all deep tissues, and blood was identified as the main path for viral dissemination. The analyses also provided information about HIV dynamics in the CNS and at the blood-brain barrier. In the accompanying Commentary, Frank Maldarelli describes how these insights into HIV’s persistence throughout the human body despite long-term ART will inform ongoing efforts to achieve complete eradication of the virus.

HIV persists throughout deep tissues with repopulation from multiple anatomical sources

Antoine Chaillon, Sara Gianella, Simon Dellicour, Stephen A. Rawlings, Timothy E. Schlub, Michelli Faria De Oliveira, Caroline Ignacio, Magali Porrachia, Bram Vrancken, and Davey M. Smith

http://jci.me/134815

Related CommentaryThe gift of a lifetime: analysis of HIV at autopsyFrank Maldarelli http://jci.me/135905

cardiologyclinical medicine

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JCI | Research: Editor’s picks

oncology

Inhibiting CoREST complex restrains Treg function and promotes antitumor immunityThe immunosuppressive functions that make Tregs essential regulators of immune homeostasis also dampen immune surveillance against tumors. Understanding the regulation of Treg gene expression may provide critical insights into Tregs’ roles in cancer and autoimmunity. Yan Xiong and colleagues examined the role of the histone-modifying CoREST repressor complex in Tregs. They determined that the CoREST component Rcor1 is key to maintaining CoREST complex–dependent functions in Tregs, including suppression of inflammatory cytokine gene expression. In syngeneic tumor models, Treg-specific loss of Rcor1 enhanced antitumor immunity, while in a cardiac allograft model, Rcor1-deficient Tregs were unable to control immune responses to the allograft. Corin, an inhibitor of the CoREST complex, also impaired Treg function and promoted antitumor immunity. In the accompanying Commentary, Luisa Morales-Nebreda, Kathryn Helmin, and Benjamin Singer predict that this identification of CoREST’s essential role in Treg function will inform development of new therapies to decrease Treg function and thereby promote antitumor immunity.

Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunityYan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, and Wayne W. Hancock http://jci.me/131375

Related CommentaryCoRESTed development of regulatory T cellsLuisa Morales-Nebreda, Kathryn A. Helmin, and Benjamin D. Singer http://jci.me/135713

c-Maf controls immunosuppressive macrophage polarization in the tumor microenvironmentImmune checkpoint inhibitors (ICIs) elicit an antitumor T cell response that can have profound clinical benefit in many cancer patients. However, tumor-associated macrophages and other suppressive immune cells in the tumor microenvironment can limit ICI efficacy, and many types of cancer display high rates of resistance to these therapies. A study led by Jun Yan identifies the transcription factor c-Maf as a regulator of immunosuppressive macrophage polarization. c-Maf expression was associated with shifts in gene expression and metabolism consistent with immunosuppressive macrophage phenotypes. Yan’s team showed that a small-molecule inhibitor of c-Maf combined with ICI treatment overcame ICI resistance in an LLC tumor model, increasing CD8+ T cell infiltration to the tumors. Moreover, the natural compound β-glucan downregulated c-Maf expression on macrophages and increased antitumor responses in mice. Jose Conejo-Garcia and Paulo Rodriguez discuss the potential for c-Maf–targeting approaches to enhance the efficacy of ICI and other immunotherapies in the accompanying Commentary.

Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancerMin Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Sabrin Albeituni, Liqing He, Xiaoling Hu, David Tieri, Eric C. Rouchka, Michito Hamada, Satoru Takahashi, Andrew A. Gibb, Goetz Kloecker, Huang-ge Zhang, Michael Bousamra II, Bradford G. Hill, Xiang Zhang, and Jun Yan http://jci.me/131335

Related Commentaryc-Maf: a bad influence in the education of macrophagesJose R. Conejo-Garcia and Paulo C. Rodriguez http://jci.me/135444

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JCI | Features

news

The ASCI recognizes rheumatologist Judith James with the Korsmeyer Award

JCI Review Series

Immunotherapy in Hematological CancersSeries Editor: Leo Luznik

Out for blood: immunotherapy of hematological cancersImmunotherapeutic strategies leveraging the immune system’s antitumor activity have become a mainstay of cancer treatment. Strategies including antibody-directed approaches, stem cell transplan-tation immunomodulatory drugs, immune checkpoint inhibitors, CAR T cells, and vaccines, have demonstrated particular success in controlling and even eradicating hematological cancers. This Review Series, developed by JCI associate editor Leo Luznik, discusses ongoing progress in immunotherapeutic targeting of hematological cancers. Reviews by Luca Vago and Ivana Gojo, Simone Minnie and Geoffrey Hill, and Stephen Ansell and Yi Lin address the state of the art in immunotherapies for acute myeloid leukemia, multiple myeloma, and lymphoma, respectively; their articles also highlight recent successes and challenges in clinical trials for these diseases. Matthew Frigault and Marcela Maus take a detailed

look at recent developments in CAR T therapies for B cell malignancies. Last but not least, Livius Penter and Catherine Wu describe how personalized antigen targeting can be applied to immunotherapeutic treatment of blood malignancies. The accompanying image, from Ansell and Lin, summarizes immuno-therapeutic strategies used in lymphoma.

Immune escape and immunotherapy of acute myeloid leukemiaLuca Vago and Ivana Gojo http://jci.me/129204

Immunotherapy of multiple myelomaSimone A. Minnie and Geoffrey R. Hill http://jci.me/129205

Immunotherapy of lymphomasStephen M. Ansell and Yi Lin http://jci.me/129206

State of the art in CAR T cell therapy for CD19+ B cell malignanciesMatthew J. Frigault and Marcela V. Maus (ASCI) http://jci.me/129208

Personal tumor antigens in blood malignancies: genomics-directed identification and targetingLivius Penter and Catherine J. Wu (ASCI) http://jci.me/129209

This year’s recipient of the Stanley J. Korsmeyer award is Judith James, professor of Medicine at the University of Oklahoma Health Science Center and member and chair of the Oklahoma Medical Research Foundation. The award recognizes Dr. James’s contributions to understanding the pathogenesis of

systemic lupus erythematosus (SLE) and other autoimmune conditions, as well as her dedication to mentorship in her home state of Oklahoma. In this issue, JCI’s executive editor Sarah Jackson interviews Dr. James about her early work, the challenges of studying SLE, and her goal of increasing Native

American representation among medical and graduate students.

Judith James honored with the 2020 Stanley J. Korsmeyer AwardSarah Jackson http://jci.me/137323

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Current research articles

autoimmunityTYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritisEric Gracey, Dominika Hromadová, Melissa Lim, Zoya Qaiyum, Michael Zeng, Yuchen Yao, Archita Srinath, Yuriy Baglaenko, Natalia Yeremenko, William Westlin, Craig Masse, Mathias Müller, Birgit Strobl, Wenyan Miao, and Robert D. Inman http://jci.me/126567

Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNSZhilin Li, Emilia A. Korhonen, Arianna Merlini, Judith Strauss, Eleonoora Wihuri, Harri Nurmi, Salli Antila, Jennifer Paech, Urban Deutsch, Britta Engelhardt, Sudhakar Chintharlapalli, Gou Young Koh, Alexander Flügel, and Kari Alitalo http://jci.me/130308

Ubiquitous antigen-specific T regulatory type 1 cells variably suppress hepatic and extrahepatic autoimmunityChannakeshava Sokke Umeshappa, Jacques Mbongue, Santiswarup Singha, Saswat Mohapatra, Jun Yamanouchi, Justin A. Lee, Roopa Hebbandi Nanjundappa, Kun Shao, Urs Christen, Yang Yang, Kristofor K. Ellestad, and Pere Santamaria http://jci.me/130670

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunityLindsay M. Webb, Shouvonik Sengupta, Claudia Edell, Zayda L. Piedra-Quintero, Stephanie A. Amici, Janiret Narvaez Miranda, Makenzie Bevins, Austin Kennemer, Georgios Laliotis, Philip N. Tsichlis, and Mireia Guerau-de-Arellano http://jci.me/131254

Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunitySimone Dertschnig, Pamela Evans, Pedro Santos e Sousa, Teresa Manzo, Ivana R. Ferrer, Hans J. Stauss, Clare L. Bennett, and Ronjon Chakraverty http://jci.me/133102

bone biologyParathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota p. 2Jau-Yi Li, Mingcan Yu, Subhashis Pal, Abdul Malik Tyagi, Hamid Dar, Jonathan Adams, M. Neale Weitzmann, Rheinallt M. Jones, and Roberto Pacifici (ASCI) http://jci.me/133473

cardiologyPrevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy p. 4Eric Himelman, Mauricio A. Lillo, Julie Nouet, J. Patrick Gonzalez, Qingshi Zhao, Lai-Hua Xie, Hong Li, Tong Liu, Xander H.T. Wehrens, Paul D. Lampe, Glenn I. Fishman, Natalia Shirokova, Jorge E. Contreras, and Diego Fraidenraich http://jci.me/128190

clinical medicineDistinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseasesAdriana A. de Jesus, Yangfeng Hou, Stephen Brooks, Louise Malle, Angelique Biancotto, Yan Huang, Katherine R. Calvo, Bernadette Marrero, Susan Moir, Andrew J. Oler, Zuoming Deng, Gina A. Montealegre Sanchez, Amina Ahmed, Eric Allenspach, Bita Arabshahi, Edward Behrens, Susanne Benseler, Liliana Bezrodnik, Sharon Bout-Tabaku, AnneMarie C. Brescia, Diane Brown, Jon M. Burnham, Maria Soledad Caldirola, Ruy Carrasco, Alice Y. Chan, Rolando Cimaz, Paul Dancey, Jason Dare, Marietta DeGuzman, Victoria Dimitriades, Ian Ferguson, Polly Ferguson, Laura Finn, Marco Gattorno, Alexei A. Grom, Eric P. Hanson, Philip J. Hashkes, Christian M. Hedrich, Ronit Herzog, Gerd Horneff, Rita Jerath, Elizabeth Kessler, Hanna Kim, Daniel J. Kingsbury, Ronald M. Laxer, Pui Y. Lee, Min Ae Lee-Kirsch, Laura Lewandowski, Suzanne Li, Vibke Lilleby, Vafa Mammadova, Lakshmi N. Moorthy, Gulnara Nasrullayeva, Kathleen M. O’Neill, Karen Onel, Seza Ozen, Nancy Pan, Pascal Pillet, Daniela G.P. Piotto, Marilynn G. Punaro, Andreas Reiff, Adam Reinhardt, Lisa G. Rider, Rafael Rivas-Chacon, Tova Ronis, Angela Rösen-Wolff, Johannes Roth, Natasha Mckerran Ruth, Marite Rygg, Heinrike Schmeling, Grant Schulert, Christiaan Scott, Gisella Seminario, Andrew Shulman, Vidya Sivaraman, Mary Beth Son, Yuriy Stepanovskiy, Elizabeth Stringer, Sara Taber, Maria Teresa Terreri, Cynthia Tifft, Troy Torgerson, Laura Tosi, Annet Van Royen-Kerkhof, Theresa Wampler Muskardin, Scott W. Canna, and Raphaela Goldbach-Mansky (ASCI) http://jci.me/129301

Plasminogen as a prognostic biomarker for HBV-related acute-on-chronic liver failureDaxian Wu, Sainan Zhang, Zhongyang Xie, Er’mei Chen, Qunfang Rao, Xiaoli Liu, Kaizhou Huang, Jing Yang, Lanlan Xiao, Feiyang Ji, Zhengyi Jiang, Yalei Zhao, Xiaoxi Ouyang, Danhua Zhu, Xiahong Dai, Zhouhua Hou, Bingjie Liu, Binbin Deng, Ning Zhou, Hainv Gao, Zeyu Sun, and Lanjuan Li http://jci.me/130197

High residual C-peptide likely contributes to glycemic control in type 1 diabetesMichael R. Rickels, Carmella Evans-Molina, Henry T. Bahnson, Alyssa Ylescupidez, Kristen J. Nadeau, Wei Hao, Mark A. Clements, Jennifer L. Sherr, Richard E. Pratley, Tamara S. Hannon, Viral N. Shah, Kellee M. Miller, Carla J. Greenbaum, and the T1D Exchange β-Cell Function Study Group http://jci.me/134057

HIV persists throughout deep tissues with repopulation from multiple anatomical sources p. 4Antoine Chaillon, Sara Gianella, Simon Dellicour, Stephen A. Rawlings, Timothy E. Schlub, Michelli Faria De Oliveira, Caroline Ignacio, Magali Porrachia, Bram Vrancken, and Davey M. Smith http://jci.me/134815

endocrinologyLeptin mediates postprandial increases in body temperature through hypothalamus–adrenal medulla–adipose tissue crosstalkRachel J. Perry, Kun Lyu, Aviva Rabin-Court, Jianying Dong, Xiruo Li, Yunfan Yang, Hua Qing, Andrew Wang, Xiaoyong Yang, and Gerald I. Shulman (ASCI) http://jci.me/134699

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Current research articles

gastroenterologyBruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitisLiming Mao, Atsushi Kitani, Eitaro Hiejima, Kim Montgomery-Recht, Wenchang Zhou, Ivan Fuss, Adrian Wiestner, and Warren Strober (ASCI) http://jci.me/128322

Pancreatic triglyceride lipase mediates lipotoxic systemic inflammationCristiane de Oliveira, Biswajit Khatua, Pawan Noel, Sergiy Kostenko, Arup Bag, Bijinu Balakrishnan, Krutika S. Patel, Andre A. Guerra, Melissa N. Martinez, Shubham Trivedi, Ann McCullough, Dora M. Lam-Himlin, Sarah Navina, Douglas O. Faigel, Norio Fukami, Rahul Pannala, Anna Evans Phillips, Georgios I. Papachristou, Erin E. Kershaw, Mark E. Lowe, and Vijay P. Singh http://jci.me/132767

Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancerYadong Xie, Yifan Zhao, Lei Shi, Wei Li, Kun Chen, Min Li, Xia Chen, Haiwei Zhang, Tiantian Li, Yu Matsuzawa-Ishimoto, Xiaomin Yao, Dianhui Shao, Zunfu Ke, Jian Li, Yan Chen, Xiaoming Zhang, Jun Cui, Shuzhong Cui, Qibin Leng, Ken Cadwell, Xiaoxia Li, Hong Wei, Haibing Zhang, Huabin Li, and Hui Xiao http://jci.me/133264

hematologyTargeting AML-associated FLT3 mutations with a type I kinase inhibitorLaQuita M. Jones, Katelyn Melgar, Lyndsey Bolanos, Kathleen Hueneman, Morgan M. Walker, Jian-Kang Jiang, Kelli M. Wilson, Xiaohu Zhang, Jian Shen, Fan Jiang, Patrick Sutter, Amy Wang, Xin Xu, Gregory J. Tawa, Scott B. Hoyt, Mark Wunderlich, Eric O’Brien, John P. Perentesis, Daniel T. Starczynowski, and Craig J. Thomas http://jci.me/127907

Steroid resistance in Diamond Blackfan anemia associates with p57Kip2 dysregulation in erythroid progenitorsRyan J. Ashley, Hongxia Yan, Nan Wang, John Hale, Brian M. Dulmovits, Julien Papoin, Meagan E. Olive, Namrata D. Udeshi, Steven A. Carr, Adrianna Vlachos, Jeffrey M. Lipton, Lydie Da Costa, Christopher Hillyer, Sandrina Kinet, Naomi Taylor, Narla Mohandas, Anupama Narla, and Lionel Blanc http://jci.me/132284

Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2Ritika Dutta, Tian Yi Zhang, Thomas Köhnke, Daniel Thomas, Miles Linde, Eric Gars, Melissa Stafford, Satinder Kaur, Yusuke Nakauchi, Raymond Yin, Armon Azizi, Anupama Narla, and Ravindra Majeti (ASCI) http://jci.me/133344

hepatologyEpithelial splicing regulatory protein 2–mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitisJeongeun Hyun, Zhaoli Sun, Ali Reza Ahmadi, Sushant Bangru, Ullas V. Chembazhi, Kuo Du, Tianyi Chen, Hidekazu Tsukamoto, Ivan Rusyn, Auinash Kalsotra, and Anna Mae Diehl (ASCI) http://jci.me/132691

immunologyVisceral adipose NLRP3 impairs cognition in obesity via IL-1R1 on CX3CR1+ cellsDe-Huang Guo, Masaki Yamamoto, Caterina M. Hernandez, Hesam Khodadadi, Babak Baban, and Alexis M. Stranahan http://jci.me/126078

infectious diseaseCapsular glycan recognition provides antibody-mediated immunity against tuberculosisTingting Chen, Caroline Blanc, Yanyan Liu, Elise Ishida, Sarah Singer, Jiayong Xu, Maju Joe, Elizabeth R. Jenny-Avital, John Chan, Todd L. Lowary, and Jacqueline M. Achkar http://jci.me/128459

nephrologyClaudin-2 deficiency associates with hypercalciuria in mice and human kidney stone diseaseJoshua N. Curry, Matthew Saurette, Masomeh Askari, Lei Pei, Michael B. Filla, Megan R. Beggs, Peter S.N. Rowe, Timothy Fields, Andre J. Sommer, Chizu Tanikawa, Yoichiro Kamatani, Andrew P. Evan, Mehdi Totonchi, R. Todd Alexander, Koichi Matsuda, and Alan S.L. Yu (ASCI) http://jci.me/127750

neuroscienceProfilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regeneration p. 3Rita Pinto-Costa, Sara C. Sousa, Sérgio C. Leite, Joana Nogueira-Rodrigues, Tiago Ferreira da Silva, Diana Machado, Joana Marques, Ana Catarina Costa, Márcia A. Liz, Francesca Bartolini, Pedro Brites, Mercedes Costell, Reinhard Fässler, and Mónica M. Sousa http://jci.me/125771

An endocannabinoid-regulated basolateral amygdala–nucleus accumbens circuit modulates sociabilityOakleigh M. Folkes, Rita Báldi, Veronika Kondev, David J. Marcus, Nolan D. Hartley, Brandon D. Turner, Jade K. Ayers, Jordan J. Baechle, Maya P. Misra, Megan Altemus, Carrie A. Grueter, Brad A. Grueter, and Sachin Patel (ASCI) http://jci.me/131752

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Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease p. 2Ethan R. Roy, Baiping Wang, Ying-wooi Wan, Gabriel Chiu, Allysa Cole, Zhuoran Yin, Nicholas E. Propson, Yin Xu, Joanna L. Jankowsky, Zhandong Liu, Virginia M.-Y. Lee, John Q. Trojanowski, Stephen D. Ginsberg, Oleg Butovsky, Hui Zheng, and Wei Cao http://jci.me/133737

oncologySuppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinomaKewen Hu, Kun Li, Jing Lv, Jie Feng, Jing Chen, Haigang Wu, Feixiong Cheng, Wenhao Jiang, Jieqiong Wang, Haixiang Pei, Paul J. Chiao, Zhenyu Cai, Yihua Chen, Mingyao Liu, and Xiufeng Pang http://jci.me/124049

Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1Leiming Wang, Mafei Xu, Chung-Yang Kao, Sophia Y. Tsai, and Ming-Jer Tsai http://jci.me/126327

The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreasKarmele Valencia, Oihane Erice, Kaja Kostyrko, Simone Hausmann, Elizabeth Guruceaga, Anuradha Tathireddy, Natasha M. Flores, Leanne C. Sayles, Alex G. Lee, Rita Fragoso, Tian-Qiang Sun, Adrian Vallejo, Marta Roman, Rodrigo Entrialgo-Cadierno, Itziar Migueliz, Nerea Razquin, Puri Fortes, Fernando Lecanda, Jun Lu, Mariano Ponz-Sarvise, Chang-Zheng Chen, Pawel K. Mazur, E. Alejandro Sweet-Cordero, and Silvestre Vicent http://jci.me/129012

HPV16 drives cancer immune escape via NLRX1-mediated degradation of STINGXiaobo Luo, Christopher R. Donnelly, Wang Gong, Blake R. Heath, Yuning Hao, Lorenza A. Donnelly, Toktam Moghbeli, Yee Sun Tan, Xin Lin, Emily Bellile, Benjamin A. Kansy, Thomas E. Carey, J. Chad Brenner, Lei Cheng, Peter J. Polverini, Meredith A. Morgan, Haitao Wen, Mark E. Prince, Robert L. Ferris, Yuying Xie, Simon Young, Gregory T. Wolf, Qianming Chen, and Yu L. Lei http://jci.me/129497

Genome-wide plasma DNA methylation features of metastatic prostate cancerAnjui Wu, Paolo Cremaschi, Daniel Wetterskog, Vincenza Conteduca, Gian Marco Franceschini, Dimitrios Kleftogiannis, Anuradha Jayaram, Shahneen Sandhu, Stephen Q. Wong, Matteo Benelli, Samanta Salvi, Giorgia Gurioli, Andrew Feber, Mariana Buongermino Pereira, Anna Maria Wingate, Enrique Gonzalez-Billalebeita, Ugo De Giorgi, Francesca Demichelis, Stefano Lise, and Gerhardt Attard http://jci.me/130887

Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancerHimisha Beltran, Alessandro Romanel, Vincenza Conteduca, Nicola Casiraghi, Michael Sigouros, Gian Marco Franceschini, Francesco Orlando, Tarcisio Fedrizzi, Sheng-Yu Ku, Emma Dann, Alicia Alonso, Juan Miguel Mosquera, Andrea Sboner, Jenny Xiang, Olivier Elemento, David M. Nanus, Scott T. Tagawa, Matteo Benelli, and Francesca Demichelis http://jci.me/131041

Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer p. 5Min Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Sabrin Albeituni, Liqing He, Xiaoling Hu, David Tieri, Eric C. Rouchka, Michito Hamada, Satoru Takahashi, Andrew A. Gibb, Goetz Kloecker, Huang-ge Zhang, Michael Bousamra II, Bradford G. Hill, Xiang Zhang, and Jun Yan http://jci.me/131335

Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity p. 5Yan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, and Wayne W. Hancock http://jci.me/131375

Genomics of lethal prostate cancer at diagnosis and castration resistanceJoaquin Mateo, George Seed, Claudia Bertan, Pasquale Rescigno, David Dolling, Ines Figueiredo, Susana Miranda, Daniel Nava Rodrigues, Bora Gurel, Matthew Clarke, Mark Atkin, Rob Chandler, Carlo Messina, Semini Sumanasuriya, Diletta Bianchini, Maialen Barrero, Antonella Petermolo, Zafeiris Zafeirou, Mariane Fontes, Raquel Perez-Lopez, Nina Tunariu, Ben Fulton, Robert Jones, Ursula McGovern, Christy Ralph, Mohini Varughese, Omi Parikh, Suneil Jain,.Tony Elliott, Shahneen Sandhu, Nuria Porta, Emma Hall, Wei Yuan, Suzanne Carreira, and Johann S. de Bono http://jci.me/132031

0phthalmologyNeogenin neutralization prevents photoreceptor loss in inherited retinal degenerationJason Charish, Alireza P. Shabanzadeh, Danian Chen, Patrick Mehlen, Santhosh Sethuramanujam, Hidekiyo Harada, Vera L. Bonilha, Gautam Awatramani, Rod Bremner, and Philippe P. Monnier http://jci.me/125898

pulmonologyCystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation p. 2Guadalupe Ortiz-Muñoz, Michelle A. Yu, Emma Lefrançais, Beñat Mallavia, Colin Valet, Jennifer J. Tian, Serena Ranucci, Kristin M. Wang, Zhe Liu, Nicholas Kwaan, Diana Dawson, Mary Ellen Kleinhenz, Fadi T. Khasawneh, Peter M. Haggie, Alan S. Verkman, and Mark R. Looney (ASCI) http://jci.me/129635

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Visualization of antidepressant analog in the brain 12

Sex-specific effects of EPO on diet-induced obesity 13

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

April 2020

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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, Nobuhiko Kamada, Celina G. Kleer, Carey Lumeng, Lona Mody, Bethany B. Moore, Marina Pasca di Magliano, Subramaniam Pennathur, Darleen Sandoval, Andrew Tai, Weiping ZouExecutive EditorSarah C. JacksonSenior Science EditorCorinne WilliamsComputational BiologistAlexey NesvizhskiiJCI Insight ScholarsHannah Bell, Fred Shen, Andrea D. Thompson

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This MonthApril 2020

For JCI Insight online: jci.me/insight/5/5jci.me/insight/5/6

Bethany Moore, PhD, Associate Editor, is the Galen B Toews, M.D., Collegiate Professor of Internal Medicine, Interim Chair of Microbi-ology and Immunology, and principal investi-gator for the T32 grant that supports the Grad-uate Program in Immunology at the University of Michigan. Dr. Moore’s research has focused on the pathogenesis of pulmonary fibrosis, and she has studied chemokines, eicosanoids, matricellular proteins, fibrocytes, microbiome dysbiosis, and viral infections as profibrotic

mediators. In her work on stem cell transplantation, she has focused on the recon-stitution of innate and adaptive immunity using both bacterial and viral infections as model systems. More recently, her laboratory has studied influenza-bacteria coinfections and the contribution of myeloid cells to diabetic wound healing.

Publication highlights in this issue denDekker AD, Davis FM, Joshi AD, Wolf SJ, Allen R, Lipinski J, Nguyen B, Kirma J, Nycz D, Bermick J, Moore BB, Gudjonsson JE, Kunkel SL, Gallagher KA. TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF. JCI Insight. 2020;5(5):e132306.

Suresh MV, Dolgachev VA, Zhang B, Balijepalli S, Swamy S, Mooliyil J, Kralovich G, Thomas B, Machado-Aranda D, Karmakar M, Lalwani S, Subramanian A, Anantharam A, Moore BB, Raghavendran K. TLR3 absence confers increased survival with improved macrophage activity against pneumonia. JCI Insight. 2019;4(23):e131195.

Wilke CA, Chadwick MM, Chan PR, Moore BB, Zhou X. Stem cell transplantation impairs dendritic cell trafficking and herpesvirus immunity. JCI Insight. 2019;4(18):e130210.

O’Dwyer DN, Zhou X, Wilke CA, Xia M, Falkowski NR, Norman KC, Arnold KB, Huffnagle GB, Murray S, Erb-Downward JR, Yanik GA, Moore BB, Dickson RP. Lung dys-biosis, inflammation, and injury in hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2019;198(10):1312–1321.

Martínez-Colón GJ, Warheit-Niemi H, Gurczynski SJ, Taylor QM, Wilke CA, Podsiad AB, Crespo J, Bhan U, Moore BB. Influenza-induced immune suppression to methicillin- resistant Staphylococcus aureus is mediated by TLR9. PLoS Pathog. 2019;15(1):e1007560.

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Editor’s picks

on the jci insight cover gastroenterology

Aim2 regulates CD8+ T cell infiltration of gastric metaplastic lesionsGastrointestinal cancer development is preceded by chronic inflammation, which can result from a variety of conditions, including long-term Helicobacter infection; however, the factors that drive this transition are unclear. Mohamad El-Zaatari and colleagues observed that the inflammasome molecule absent in melanoma 2 (Aim2) is upregulated in patients with gastric cancer and in spasmolytic polypeptide–express-ing metaplasia of mice chronically infected with H. felis. In H. felis–infected mice, Aim2 deficiency did not alter inflammasome function but increased gastric CD8+ T cells, thereby exacerbating metaplasia. Gastric CD8+ T cells in the context of Aim2 deficiency had reduced homing receptor expression, which was potentially the result of increased CXCL16 expression in B cells and not a response to IFN-β or dendritic cells. Cumula-tively, these results reveal that Aim2 regulates infiltration of CD8+ T cells into inflamed tissue in an inflammasome-independent manner. The cover image shows T cell infiltration (CD3 staining in brown) in the gastric mucosa of Aim2–/– mice following 6 months of H. felis infection.

Osteoclast-derived IGF1 in Paget’s disease drives abnormal bone formation

Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cellsMohamad El-Zaatari, Shrinivas Bishu, Min Zhang, Helmut Grasberger, Guoqing Hou, Henry Haley, Brock Humphries, Li-Jyun Syu, Andrzej A. Dlugosz, Kathy Luker, Gary D. Luker, Kathryn Eaton, Nobuhiko Kamada, Marilia Cascalho, and John Y. Kao http://jci.me/94035

bone biology

Abnormal bone remodeling in Paget’s disease (PD) results in localized areas of enlarged, weaker bone that is prone to fracture, deformity, and other complications. Dysfunctional bone-resorbing osteoclasts are linked to disease, and previous studies have shown elevated levels of osteo-clast-derived IGF1 in PD patients and murine models. Kazuaki Miyagawa and colleagues evaluated the effect of osteoclast-specific Igf1 deletion in WT and PD model mice. Pagetic bone

lesions (PDLs) were present in PD mice; however, PDLs did not form in PD mice lacking IGF1. In addition, IGF1 deficiency in both WT and PD mice decreased bone volume (see the accompanying image) and bone formation rates in PD mice, which was linked to a decrease in ephrinB2 and EphB4. The PD-associated increase in osteoclast-generated IGF1 was determined to be induced by IL-6. Together, these results demonstrate that increased osteoclast IGF1 directly promotes abnormal bone

formation in PD via enhanced ephrinB2/EphB4 signaling.

Osteoclast-derived IGF1 is required for pagetic lesion formation in vivoKazuaki Miyagawa, Yasuhisa Ohata, Jesus Delgado-Calle, Jumpei Teramachi, Hua Zhou, David D. Dempster, Mark A. Subler, Jolene J. Windle, John M. Chirgwin, G. David Roodman, and Noriyoshi Kurihara htpp://jci.me/133113

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JCI Insight | Editor’s picks

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neuroscienceimmunology

immunology

High-resolution visualization of S-citalopram distribution in the brainThe precise location and distribution of drugs within tissues, especially the brain, can influence response and the dose required. Masato Tanuma, Atsushi Kasai, Kazuki Bando, and colleagues developed a surface-enhanced Raman scattering–based (SERS-based) method that allows direct, high-resolution, in situ visualization of low–molecular weight compounds in the brain. Specifically, the authors synthesized an alkynylated form of the selective serotonin reuptake inhibitor S-citalopram (Alk-S-Cit) that has brain transitivity and inhibition of serotonin reuptake similar to those of S-Cit. Using SERS imaging with silver nanoparticles, the authors were able to visualize Alk-S-Cit in the coronal mouse brain. Moreover, combining SERS with fluorescence microscopy showed the compound in adjacent neuronal membranes, as well as in blood vessels and brain parenchyma (see the accompanying image). This proof-of-concept study supports SERS imaging as a means to determine tissue localization and distribution of low–molecular weight drugs.

Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brainMasato Tanuma, Atsushi Kasai, Kazuki Bando, Naoyuki Kotoku, Kazuo Harada, Masafumi Minoshima, Kosuke Higashino, Atsushi Kimishima, Masayoshi Arai, Yukio Ago, Kaoru Seiriki, Kazuya Kikuchi, Satoshi Kawata, Katsumasa Fujita, and Hitoshi Hashimoto htpp://jci.me/133348

Newborn and adult antibody response to influenza A virus infectionInfants are at increased susceptibility to influenza A virus (IAV) infection and have a higher incidence of severe disease and complications. The development and specificity of antibodies (Abs) in response to IAV infection influence outcome; however, the contribution of age at time of infection in IAV Ab development is not fully understood. Elene Clemens et al. evaluated Ab immunodominance in newborn and adult African green monkeys following IAV infection. Both newborn and adult animals generated high levels of hemagglutinin stem– specific Abs. While newborns and adults developed similar hemagglutinin-specific IgG dominance profiles, the patterns in the IgA and early IgM response were distinct. Avidity did not associate

with dominance in either newborn or adult animals. These results demonstrate that age influences Ab responses and can vary across isotypes, which may be linked to age-associated differences in IAV susceptibility.

Influenza-infected newborn and adult monkeys exhibit a strong primary antibody response to hemagglutinin stemElene Clemens, Davide Angeletti, Beth C. Holbrook, Masaru Kanekiyo, Matthew J. Jorgensen, Barney S. Graham, Jonathan Yewdell, and Martha A. Alexander-Miller http://jci.me/135449

CTPS1 deficiency impairs lymphocyte function and proliferationCytidine triphosphate synthase (CTPS), which is encoded by CTPS1 and CTPS2, is essential for CTP generation. CTPS activity is tightly controlled in lymphocytes and is dysregulated in cancers. CTPS1 deficiency results from a unique mutation, and patients are immunodeficient and prone to severe viral and bacterial infections. However, the effect of this mutation in patients has not been fully explored. Emmanuel Martin and colleagues performed in-depth immune phenotyping of lymphocyte subsets in 7 patients and found low numbers or absence of mucosal-associated invariant T, invariant NKT, memory B, and NK cells. TCR-induced IL-2 secretion and proliferation were markedly reduced; however, other T cell functions were not affected. The mutation is hypomorphic because CTPS1 expression and CTPS activity were diminished but not absent in patient T cells, and CTPS1-deficient T leukemia cells were unable to proliferate. This study not only characterizes CTPS1 deficiency–associated defects but also supports CTPS1 as a therapeutic target to limit pathological T cell proliferation.

Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutationEmmanuel Martin, Norbert Minet, Anne-Claire Boschat, Sylvia Sanquer, Steicy Sobrino, Christelle Lenoir, Jean Pierre de Villartay, Maria Leites-de-Moraes, Capucine Picard, Claire Soudais, Tim Bourne, Sophie Hambleton, Stephen M. Hughes, Robert F. Wynn, Tracy A. Briggs, Genomics England Research Consortium, Smita Patel, Monica G. Lawrence, Alain Fischer, Peter D. Arkwright, and Sylvain Latour http://jci.me/133880

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JCI Insight | Editor’s picks

aids/hiv

Cell-associated HIV-1 RNA predicts viral control and treatment responseWhen used consistently, antiretroviral therapy (ART) is highly successful in stopping HIV-1 replication and preventing AIDS. In adherent patients, the virus stays undetect-able in plasma but is never completely eradicated. Removal of ART results in viral rebound because of the presence of stable viral reservoirs. Alexander Pasternak and colleagues evaluated the potential of cell-associated HIV-1 RNA and DNA to predict the magnitude and time to viral rebound in HIV-infected individuals treated with temporary ART during primary infection. In this cohort, cell-associated HIV-1 RNA was independently predictive of both the virologic and immunologic response to ART, as well as viral rebound and disease progression (CD4+ T cell loss) after ART interruption. Moreover, cell-associated RNA outperformed plasma viral load, the standard test of virologic response, in predicting clinical outcomes, supporting further investigation of cell-associated RNA as a clinical marker for treatment response.

Cell-associated HIV-1 RNA predicts viral rebound and disease progression after discontinuation of temporary early ARTAlexander O. Pasternak, Marlous L. Grijsen, Ferdinand W. Wit, Margreet Bakker, Suzanne Jurriaans, Jan M. Prins, and Ben Berkhout http://jci.me/134196

metabolism

Sex-dependent metabolic response to erythropoietin in the brainIn murine models, exogenous erythropoietin (EPO) limits adverse effects of diet-induced obesity (DIO), particularly in male mice. The benefits include reduced food intake, improved glucose tolerance, and reduced white adipose tissue inflammation. However, it is not clear whether these effects are independent of EPO-mediated changes in hematocrit. Soumyadeep Dey and colleagues generated and characterized transgenic mice that overexpress EPO only in the brain (Tg21 mice). Following high-fat diet feeding, male Tg21 mice were protected from DIO and exhibited less hypothalamic inflammation (see the accompanying image) and microglial activation than WT mice. These effects were not seen in female Tg21 mice; however, both male and female mice exhibited improved glycemic control. Estrogen was linked to the reduced effects of EPO on DIO in female mice. These results show sex-specific effects of EPO on obesity and hypothalamic inflammation that are independent of EPO-regulated glycemic control and erythropoietic response.

Sex-specific brain erythropoietin regulation of mouse metabolism and hypothalamic inflammationSoumyadeep Dey, Zhenzhong Cui, Oksana Gavrilova, Xiaojie Zhang, Max Gassmann, and Constance T. Noguchi http://jci.me/134061

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Current articles

Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signalingMorgan Bridi, Hannah Schoch, Cédrick Florian, Shane G. Poplawski, Anamika Banerjee, Joshua D. Hawk, Giulia S. Porcari, Camille Lejards, Chang-Gyu Hahn, Karl-Peter Giese, Robbert Havekes, Nelson Spruston, and Ted Abel http://jci.me/92385

Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cells p. 11Mohamad El-Zaatari, Shrinivas Bishu, Min Zhang, Helmut Grasberger, Guoqing Hou, Henry Haley, Brock Humphries, Li-Jyun Syu, Andrzej A. Dlugosz, Kathy Luker, Gary D. Luker, Kathryn Eaton, Nobuhiko Kamada, Marilia Cascalho, and John Y. Kao http://jci.me/94035

Soluble (pro)renin receptor treats metabolic syndrome in mice with diet-induced obesity via interaction with PPARγFei Wang, Renfei Luo, Chang-Jiang Zou, Shiying Xie, Kexin Peng, Long Zhao, Kevin T. Yang, Chuanming Xu, and Tianxin Yang http://jci.me/128061

Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell functionDhifaf Sarhan, Jinhua Wang, Upasana Sunil Arvindam, Caroline Hallstrom, Michael R. Verneris, Bartosz Grzywacz, Erica Warlick, Bruce R. Blazar, and Jeffrey S. Miller (ASCI) http://jci.me/130155

Serine/threonine phosphatase PP2A is essential for optimal B cell functionEsra Meidan, Hao Li, Wenliang Pan, Michihito Kono, Shuilian Yu, Vasileios C. Kyttaris, Christina Ioannidis, Noe Rodriguez Rodriguez, Jose C. Crispin, Sokratis A. Apostolidis, Pui Lee, John Manis, Amir Sharabi, Maria G. Tsokos, and George C. Tsokos http://jci.me/130655

C3a receptor blockade protects podocytes from injury in diabetic nephropathyMarina Morigi, Luca Perico, Daniela Corna, Monica Locatelli, Paola Cassis, Claudia Elisa Carminati, Silvia Bolognini, Carlamaria Zoja, Giuseppe Remuzzi, Ariela Benigni, and Simona Buelli http://jci.me/131849

Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver diseasePanu K. Luukkonen, Taru Tukiainen, Anne Juuti, Henna Sammalkorpi, P.A. Nidhina Haridas, Onni Niemelä, Johanna Arola, Marju Orho-Melander, Antti Hakkarainen, Petri T. Kovanen, Om Dwivedi, Leif Groop, Leanne Hodson, Amalia Gastaldelli, Tuulia Hyötyläinen, Matej Orešič, and Hannele Yki-Järvinen http://jci.me/132158

TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOFAaron D. denDekker, Frank M. Davis, Amrita D. Joshi, Sonya J. Wolf, Ronald Allen, Jay Lipinski, Brenda Nguyen, Joseph Kirma, Dylan Nycz, Jennifer Bermick, Bethany B. Moore, Johann E. Gudjonsson, Steven L. Kunkel, and Katherine A. Gallagher (ASCI) http://jci.me/132306

The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLPSarrabeth Stone, Shuangchan Wu, Klaus-Armin Nave, and Wensheng Lin http://jci.me/132364

Impaired skeletal muscle mitochondrial bioenergetics and physical performance in chronic kidney diseaseBryan Kestenbaum, Jorge Gamboa, Sophia Liu, Amir S. Ali, Eric Shankland, Thomas Jue, Cecilia Giulivi, Lucas R. Smith, Jonathan Himmelfarb, Ian H. de Boer, Kevin Conley, and Baback Roshanravan http://jci.me/133289

Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicityUgur Eskiocak, Wilson Guzman, Benjamin Wolf, Christine Cummings, Lauren Milling, Hsin-Jung Wu, Michael Ophir, Conner Lambden, Pearl Bakhru, Dana C. Gilmore, Samantha Ottinger, Lucy Liu, William K. McConaughy, Sunny Q. He, Chao Wang, Cheuk Lun Leung, Jason Lajoie, William F. Carson IV, Nora Zizlsperger, Michael M. Schmidt, Ana C. Anderson, Piotr Bobrowicz, Thomas J. Schuetz, and Robert Tighe http://jci.me/133647

Integrative study of the upper and lower airway microbiome and transcriptome in asthmaYoojin Chun, Anh Do, Galina Grishina, Alexander Grishin, Gang Fang, Samantha Rose, Chantal Spencer, Alfin Vicencio, Eric Schadt, and Supinda Bunyavanich http://jci.me/133707

Extracellular CIRP induces macrophage endotoxin tolerance through IL-6R–mediated STAT3 activationMian Zhou, Monowar Aziz, Naomi-Liza Denning, Hao-Ting Yen, Gaifeng Ma, and Ping Wang http://jci.me/133715

BCG vaccination reduces the mortality of Mycobacterium tuberculosis–infected type 2 diabetes mellitus miceRajesh Kumar Radhakrishnan, Ramya Sivangala Thandi, Deepak Tripathi, Padmaja Paidipally, Madeline Kay McAllister, Sachin Mulik, Buka Samten, and Ramakrishna Vankayalapati http://jci.me/133788

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Current articles

Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation p. 12Emmanuel Martin, Norbert Minet, Anne-Claire Boschat, Sylvia Sanquer, Steicy Sobrino, Christelle Lenoir, Jean Pierre de Villartay, Maria Leites-de-Moraes, Capucine Picard, Claire Soudais, Tim Bourne, Sophie Hambleton, Stephen M. Hughes, Robert F. Wynn, Tracy A. Briggs, Genomics England Research Consortium, Smita Patel, Monica G. Lawrence, Alain Fischer, Peter D. Arkwright, and Sylvain Latour http://jci.me/133880

Sex-specific brain erythropoietin regulation of mouse metabolism and hypothalamic inflammation p. 13Soumyadeep Dey, Zhenzhong Cui, Oksana Gavrilova, Xiaojie Zhang, Max Gassmann, and Constance T. Noguchi http://jci.me/134061

Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsisNaomi-Liza Denning, Monowar Aziz, Atsushi Murao, Steven D. Gurien, Mahendar Ochani, Jose M. Prince, and Ping Wang http://jci.me/134172

T cell response kinetics determines neuroinfection outcomes during murine HSV infectionAisha G. Lee, Jason M. Scott, Maria Rita Fabbrizi, Xiaoping Jiang, Dorothy K. Sojka, Mark J. Miller, Megan T. Baldridge, Wayne M. Yokoyama, and Haina Shin http://jci.me/134258

Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolutionHuachun Cui, Dingyuan Jiang, Sami Banerjee, Na Xie, Tejaswini Kulkarni, Rui-Ming Liu, Steven R. Duncan, and Gang Liu http://jci.me/134539

Increased ATP synthesis might counteract hepatic lipid accumulation in acromegalyPaul Fellinger, Peter Wolf, Lorenz Pfleger, Patrik Krumpolec, Martin Krssak, Kristaps Klavins, Stefan Wolfsberger, Alexander Micko, Patricia Carey, Bettina Gürtl, Greisa Vila, Wolfgang Raber, Clemens Fürnsinn, Thomas Scherer, Siegfried Trattnig, Alexandra Kautzky-Willer, Michael Krebs,and Yvonne Winhofer http://jci.me/134638

Influenza-infected newborn and adult monkeys exhibit a strong primary antibody response to hemagglutinin stem p. 12Elene Clemens, Davide Angeletti, Beth C. Holbrook, Masaru Kanekiyo, Matthew J. Jorgensen, Barney S. Graham, Jonathan Yewdell, and Martha A. Alexander-Miller http://jci.me/135449

Prostate tumor–derived GDF11 accelerates androgen deprivation therapy–induced sarcopeniaChunliu Pan, Neha Jaiswal Agrawal, Yanni Zulia, Shalini Singh, Kai Sha, James L. Mohler, Kevin H. Eng, Joe V. Chakkalakal, John J. Krolewski, and Kent L. Nastiuk http://jci.me/127018

Glucocorticoids affect metabolic but not muscle microvascular insulin sensitivity following high versus low salt intakeMonica T.J. Schütten, Yvo H.A.M. Kusters, Alfons J.H.M. Houben, Hanneke E. Niessen, Jos op ’t Roodt, Jean L.J.M. Scheijen, Marjo P. van de Waardenburg, Casper G. Schalkwijk, Peter W. de Leeuw, and Coen D.A. Stehouwer http://jci.me/127530

Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubulesJinpeng Li, Haijie Liu, Susumu Takagi, Kyoko Nitta, Munehiro Kitada, Swayam P. Srivastava, Yuta Takagaki, Keizo Kanasaki, and Daisuke Koya http://jci.me/129034

Genomic variations in EBNA3C of EBV associate with posttransplant lymphoproliferative disorderEden M. Maloney, Vincent A. Busque, Sin Ting Hui, Jiaying Toh, Marcelo Fernandez-Vina, Sheri M. Krams, Carlos O. Esquivel, and Olivia M. Martinez http://jci.me/131644

iPSC-derived endothelial cell response to hypoxia via SDF1a/CXCR4 axis facilitates incorporation to revascularize ischemic retinaHongkwan Cho, Bria L. Macklin, Ying-Yu Lin, Lingli Zhou, Michael Lai, Grace Lee, Sharon Gerecht, and Elia J. Duh (ASCI) http://jci.me/131828

Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humansClaire Laurens, Anisha Parmar, Enda Murphy, Deborah Carper, Benjamin Lair, Pauline Maes, Julie Vion, Nathalie Boulet, Coralie Fontaine, Marie Marquès, Dominique Larrouy, Isabelle Harant, Claire Thalamas, Emilie Montastier, Sylvie Caspar-Bauguil, Virginie Bourlier, Geneviève Tavernier, Jean-Louis Grolleau, Anne Bouloumié, Dominique Langin, Nathalie Viguerie, Fabrice Bertile, Stéphane Blanc, Isabelle de Glisezinski, Donal O’Gorman, and Cedric Moro http://jci.me/131870

MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitorsDominik Marschner, Martina Falk, Nora Rebeka Javorniczky, Kathrin Hanke-Müller, Justyna Rawluk, Annette Schmitt-Graeff, Federico Simonetta, Eileen Haring, Severin Dicks, Manching Ku, Sandra Duquesne, Konrad Aumann, David Rafei-Shamsabadi, Frank Meiss, Patrick Marschner, Melanie Boerries, Robert S. Negrin, Justus Duyster, Robert Zeiser, and Natalie Köhler http://jci.me/132334

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Th17 reprogramming of T cells in systemic juvenile idiopathic arthritisLauren A. Henderson, Kacie J. Hoyt, Pui Y. Lee, Deepak A. Rao, A. Helena Jonsson, Jennifer P. Nguyen, Kayleigh Rutherford, Amélie M. Julé, Louis-Marie Charbonnier, Siobhan Case, Margaret H. Chang, Ezra M. Cohen, Fatma Dedeoglu, Robert C. Fuhlbrigge, Olha Halyabar, Melissa M. Hazen, Erin Janssen, Susan Kim, Jeffrey Lo, Mindy S. Lo, Esra Meidan, Mary Beth F. Son, Robert P. Sundel, Matthew L. Stoll, Chad Nusbaum, James A. Lederer, Talal A. Chatila, and Peter A. Nigrovic (ASCI) http://jci.me/132508

Osteoclast-derived IGF1 is required for pagetic lesion formation in vivo p. 11Kazuaki Miyagawa, Yasuhisa Ohata, Jesus Delgado-Calle, Jumpei Teramachi, Hua Zhou, David D. Dempster, Mark A. Subler, Jolene J. Windle, John M. Chirgwin, G. David Roodman (ASCI), and Noriyoshi Kurihara http://jci.me/133113

Single cell transcriptomics identifies focal segmental glomerulosclerosis remission endothelial biomarkerRajasree Menon, Edgar A. Otto, Paul Hoover, Sean Eddy, Laura Mariani, Bradley Godfrey, Celine C. Berthier, Felix Eichinger, Lalita Subramanian, Jennifer Harder, Wenjun Ju, Viji Nair, Maria Larkina, Abhijit S. Naik, Jinghui Luo, Sanjay Jain, Rachel Sealfon, Olga Troyanskaya, Nir Hacohen, Jeffrey B. Hodgin, Matthias Kretzler (ASCI), Kidney Precision Medicine Project (KPMP), and Nephrotic Syndrome Study Network (NEPTUNE) http://jci.me/133267

Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brain p. 12Masato Tanuma, Atsushi Kasai, Kazuki Bando, Naoyuki Kotoku, Kazuo Harada, Masafumi Minoshima, Kosuke Higashino, Atsushi Kimishima, Masayoshi Arai, Yukio Ago, Kaoru Seiriki, Kazuya Kikuchi, Satoshi Kawata, Katsumasa Fujita, and Hitoshi Hashimoto http://jci.me/133348

Semaglutide lowers body weight in rodents via distributed neural pathwaysSanaz Gabery, Casper G. Salinas, Sarah J. Paulsen, Jonas Ahnfelt-Rønne, Tomas Alanentalo, Arian F. Baquero, Stephen T. Buckley, Erzsébet Farkas, Csaba Fekete, Klaus S. Frederiksen, Hans Christian C. Helms, Jacob F. Jeppesen, Linu M. John, Charles Pyke, Jane Nøhr, Tess T. Lu, Joseph Polex-Wolf, Vincent Prevot, Kirsten Raun, Lotte Simonsen, Gao Sun, Anett Szilvásy-Szabó, Hanni Willenbrock, Anna Secher, and Lotte Bjerre Knudsen http://jci.me/133429

Targeting the gut barrier to prevent aging: a role for intestinal alkaline phosphataseFlorian Kühn, Fatemeh Adiliaghdam, Paul M. Cavallaro, Sulaiman R. Hamarneh, Amy Tsurumi, Raza S. Hoda, Alexander R. Munoz, Yashoda Dhole, Juan M. Ramirez, Enyu Liu, Robin Vasan, Yang Liu, Ehsan Samarbafzadeh, Rocio A. Nunez, Matthew Z. Farber, Vanita Chopra, Madhu S. Malo, Laurence G. Rahme, and Richard A. Hodin (ASCI) http://jci.me/134049

Cell-associated HIV-1 RNA predicts viral rebound and disease progression after discontinuation of temporary early ART p. 13Alexander O. Pasternak, Marlous L. Grijsen, Ferdinand W. Wit, Margreet Bakker, Suzanne Jurriaans, Jan M. Prins, and Ben Berkhout http://jci.me/134196

A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsyAriane E. Rhone, Christopher K. Kovach, Gail I.S. Harmata, Alyssa W. Sullivan, Daniel Tranel, Michael A. Ciliberto, Matthew A. Howard, George B. Richerson, Mitchell Steinschneider, John A. Wemmie, and Brian J. Dlouhy http://jci.me/134852

Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodelingChristian Riehle, Eric T. Weatherford, Adam R. Wende, Bharat P. Jaishy, Alec W. Seei, Nicholas S. McCarty, Monika Rech, Qian Shi, Gopireddy R. Reddy, William J. Kutschke, Karen Oliveira, Karla Maria Pires, Joshua C. Anderson, Nikolaos A. Diakos, Robert M. Weiss, Morris F. White, Stavros G. Drakos, Yang K. Xiang, and E. Dale Abel (ASCI) http://jci.me/134920

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunctionYing Wang, Soichi Sano, Yoshimitsu Yura, Zhonghe Ke, Miho Sano, Kosei Oshima, Hayato Ogawa, Keita Horitani, Kyung-Duk Min, Emiri Miura-Yura, Anupreet Kour, Megan A. Evans, Maria A. Zuriaga, Karen K. Hirschi, Jose J. Fuster, Eric M. Pietras, Kenneth Walsh http://jci.me/135204

The omentum of obese girls harbors small adipocytes and browning transcriptsElena Tarabra, Jessica Nouws, Alla Vash-Margita, Geoffrey S. Nadzam, Rachel Goldberg, Michelle Van Name, Bridget Pierpont, James R. Knight, Gerald I. Shulman, and Sonia Caprio http://jci.me/135448

TGFβ-driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse modelDavi A.G. Mázala, James S. Novak, Marshall W. Hogarth, Marie Nearing, Prabhat Adusumalli, Christopher B. Tully, Nayab F. Habib, Heather Gordish-Dressman, Yi-Wen Chen, Jyoti K. Jaiswal, and Terence A. Partridge http://jci.me/135703

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