jci.org/this-month

Also in this issue:

mTORC1 mediates adipose tissue browning 4

Therapeutic modulation of the blood-brain barrier 5

Neuropeptide Y in asthma 6

JCI Insight 11

A summary of the most recent articles in the Journal of Clinical investigation and JCi insight

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This MonthMay 2016

A pharmacological approach for treating dwarfism p. 1

http://www.uhhospitals.org/services/harrington-discovery-institute/programs-and-initiatives/harrington-scholar-innovator-program

j c i . o r g / t h i s - m o n t h m a y 2 0 1 6 1

For the JCi and JCi insighteditorHoward A. Rockman

executive editorSarah C. Jackson

science editorsJillian Hurst, Corinne Williams

For the JCiDeputy editorsGarnett Kelsoe, Bryan L. Roth

Associate editorsSoman N. Abraham, Vann Bennett, Gerard C. Blobe, Kathleen M. Caron, Marc G. Caron, John P. Chute, Thomas M. Coffman, Anna Mae Diehl, Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Thomas Weber, Yiping Yang

Clinical Medicine Associate editorsMichael A. Morse, Andrew J. Muir, Scott M. Palmer, Mark A. Stacy

Asia editorDavid M. Virshup

Chair, executive CouncilRobert J. Lefkowitz

BiostatisticiansCynthia Coffman, Maren Olsen

BioethicistArthur L. Caplan

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editor at largeUshma S. Neill

issn 2324-7703 (print)issn 2325-4556 (online)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.

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This MonthMay 2016

A tyrosine kinase inhibitor shows promise in a preclinical model of dwarfism

On the JCI cover

Dwarfism can be caused by genetic mutations that affect bone growth or growth hormone production. The most common form of dwarfism is achondroplasia, which is caused by a gain-of-function mutation in FGFR3 that disrupts proliferation and differentiation in the bone growth plate. As a potential therapy, a research team led by Laurence Legeai-Mallet examined the tyrosine kinase inhibitor NVP-BGJ398, which targets members of the FGF receptor family, in a mouse model of achondroplasia expressing Fgfr3Y367C. In culture, NVP-BGJ398 inhibited FGFR3 activity and rescued ex vivo growth

of embryonic femurs from Fgfr3Y367C/+ mice. The research team subsequently tested treatment of newborn Fgfr3Y367C/+ mice for 15 days with NVP-BGJ398 and found that mice developed longer limbs relative to untreated controls. Moreover, NVP-BGJ398 increased chondrocyte proliferation in growth-plate cartilage of the femurs and tibia and was associated with elevated angiogenesis and differentiation markers. Treatment also rescued intervertebral disc and vertebrae anomalies and increased the length of the lumbar L4–L6 segment. The authors compared postnatal treatment with NVP-BGJ398 to treatment with BMN111, a C-natriuretic peptide analog that is currently in a phase 2 trial for achondroplasia in their preclinical mouse model. These studies suggest that directly targeting hyperactive FGFR3 signaling may provide an early treatment option for achondroplasia. The accompanying image shows safranin O staining of a lumbar intervertebral disc from an Fgfr3Y367C/+ mouse treated with NVP-BGJ398. Image credit: Davide Komla-Ebri.

Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse modelDavide Komla-Ebri, Emilie Dambroise, Ina Kramer, Catherine Benoist-Lasselin, Nabil Kaci, Cindy Le Gall, Ludovic Martin, Patricia Busca, Florent Barbault, Diana Graus-Porta, Arnold Munnich, Michaela Kneissel, Federico Di Rocco, Martin Biosse-Duplan, and Laurence Legeai-Mallet http://jci.me/83926

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bone biology

Striking a balance between hedgehog and Wnt in synovial joints

synovial joints function as sites of articulation between adjacent bones. The tissues that compose the synovial joint arise from a set of interzone cells; however, the signaling pathways governing differentiation are poorly understood. Jason Rockel and colleagues investigated how hedgehog (HH) and Wnt/β-catenin signaling pathways regulate interzone cells during joint morphogenesis. By manipulating interzone cell expression of HH and Wnt/β-catenin pathway genes in mice, they demonstrated that HH signaling selectively inhibits β-catenin target gene expression, including Fgf18,

the loss of which is associated with cartilage degeneration in osteoarthritis. Mechanistically, HH signaling induces expression of a dominant negative form of the transcription factor TCF7L2 (dnTCFL2), leading to increased expression of osteoarthritis-associated catabolic enzymes. Importantly, β-catenin activation attenuated cartilage degenera-tion (see the accompanying image), indicating that agents that counteract HH signaling or promote β-catenin signaling could be used to treat osteoarthritis-associated cartilage degeneration.

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritisJason S. Rockel, Chunying Yu, Heather Whetstone, April M. Craft, Katherine Reilly, Henry Ma, Hidetoshi Tsushima, Vijitha Puviindran, Mushriq Al-Jazrawe, Gordon M. Keller, and Benjamin A. Alman http://jci.me/80205

oncology

Prevention of platelet extravasation improves response to antiangiogenic therapy

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawalMonika Haemmerle, Justin Bottsford-Miller, Sunila Pradeep, Morgan L. Taylor, Hyun-Jin Choi, Jean M. Hansen, Heather J. Dalton, Rebecca L. Stone, Min Soon Cho, Alpa M. Nick, Archana S. Nagaraja, Tony Gutschner, Kshipra M. Gharpure, Lingegowda S. Mangala, Rajesha Rupaimoole, Hee Dong Han, Behrouz Zand, Guillermo N. Armaiz-Pena, Sherry Y. Wu, Chad V. Pecot, Alan R. Burns, Gabriel Lopez-Berestein, Vahid Afshar-Kharghan, and Anil K. Sood http://jci.me/85086

Antiangiogenic therapies are used to treat a variety of cancers; however, in patients with ovarian cancer there is growing evidence that such therapies may result in increased angiogenesis and tumor growth upon therapy withdrawal. In this issue, Monika Haemmerle, Justin Bottsford-Miller, and colleagues used murine models of ovarian cancer to examine the effects of therapy withdrawal compared with those of continuous therapy with antiangiogenic agents. They found that cessation of antiangiogenic therapy markedly enhanced tumor growth and that this was associated with increased tumor hypoxia, angiogenesis, vascular leakage, and increased platelet infiltration into tumors. Notably, lowering platelet counts prevented tumor rebound after therapy withdrawal. Haemmerle, Bottsford-Miller, and colleagues demonstrated that focal adhesion kinase (FAK) was required for platelet extravasation from vessels into the tumor. Moreover, tumor rebound growth was prevented by FAK inhibitor administration after withdrawal of antiangiogenic therapy.

research

Editor’s picks

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JCI | Research: Editor’s picks

nephrology

Loss of mTORC2 in the distal tubule impairs potassium handlingsignaling by the mtoRC pathway mediates a diverse array of cellular activities. In this issue, Florian Grahammer and colleagues investigated the role of mTORC2 in the kidney with mice specifically lacking the mTORC2 component Rictor in the distal tubule. They found that mice lacking mTORC2 adequately reduced sodium excretion in response to decreased dietary sodium but did not increase excretion of potassium in response to a high-potassium diet, resulting in hyperkalemia. Mechanistically, loss of mTORC2 signaling led to the loss of the renal outer medullary potassium channel from the apical side of the distal tubule but did not alter activity of the sodium transporter epithelial sodium channel.

mTORC2 critically regulates renal potassium handlingFlorian Grahammer, Viatcheslav Nesterov, Azaz Ahmed, Frederic Steinhardt, Lukas Sandner, Frederic Arnold, Tomke Cordts, Silvio Negrea, Marko Bertog, Marcus A. Ruegg, Michael N. Hall, Gerd Walz, Christoph Korbmacher, Ferruh Artunc, and Tobias B. Huber http://jci.me/80304

Vagus nerve stimulation protects against kidney ischemia-reperfusion injurythe cholinergic antiinflammatory pathway is the efferent arm of a vagal reflex that regulates the intensity and duration of inflammation. Tsuyoshi Inoue, Chikara Abe, and colleagues examined whether vagal antiinflammatory effects could be harnessed to reduce kidney ischemia-reperfusion injury (IRI). They found that electrical stimulation of vagal afferents or efferents 24 hours before ischemia attenuated acute kidney injury (AKI) (see the accompanying image) and decreased plasma TNF levels. Splenectomy prior to vagus nerve stimulation (VNS) and IRI abolished these effects, indicating that the spleen was required. VNS was ineffective in mice lacking the α7 nicotinic acetylcholine receptor (α7nAChR). Moreover, transfer of α7nAChR-expressing splenocytes from VNS-conditioned mice protected unconditioned mice against IRI, indicating the importance of α7nAChR-expressing immune cells in VNS protection. In the accompanying Commentary, Simon Atkinson discusses how VNS could potentially be used as a therapeutic intervention in AKI.

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytesTsuyoshi Inoue, Chikara Abe, Sun-sang J. Sung, Stefan Moscalu, Jakub Jankowski, Liping Huang, Hong Ye, Diane L. Rosin, Patrice G. Guyenet, and Mark D. Okusa http://jci.me/83658

Related CommentaryA wandering path toward prevention for acute kidney injurySimon J. Atkinson http://jci.me/86826

Female sex protects against ischemic injury in kidney allograftsthe sex of the donor and recipient in human renal transplantation is associated with allograft function and survival. David Aufhauser Jr., Zhonglin Wang, and colleagues used murine renal transplant models to examine the mechanisms underlying the sexual dimorphism of kidney transplant function and found that female mice showed greater tolerance to ischemia-reperfusion injury (IRI) than did male mice. Loss of sex hormones in either sex resulted in an intermediate phenotype. In mice receiving kidney transplants, the sex of the donor and recipient affected IRI. Notably, loss of estrogen receptor α (ERα) in female recipients exacerbated IRI, while estrogen supplementation prior to injury was protective. Finally, a multivariable logistic regression analysis of human kidney transplant recipients demonstrated that male recipients had increased delayed graft function compared with that observed in female recipients. In the accompanying Commentary, Sanjeev Noel, Hamid Rabb, and colleagues discuss the implications of these findings for improving kidney transplantation outcomes.

Improved renal ischemia tolerance in females influences kidney transplantation outcomesDavid D. Aufhauser Jr., Zhonglin Wang, Douglas R. Murken, Tricia R. Bhatti, Yanfeng Wang, Guanghui Ge, Robert R. Redfield III, Peter L. Abt, Liqing Wang, Nikolaos Svoronos, Arwin Thomasson, Peter P. Reese, Wayne W. Hancock, and Matthew H. Levine http://jci.me/84712

Related CommentarySex and the single transplanted kidneySanjeev Noel, Niraj M. Desai, Abdel Hamad, and Hamid Rabb http://jci.me/87428

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JCI | Research: Editor’s picks

endocrinology

White adipose tissue “browning” via mTORC1Adipocyte functions are regulated by insulin, which stimulates insulin receptors to induce energy storage in white adipose tissue (WAT), and catecholamines, which stimulate β-adrenergic receptors (βARs) to induce energy consumption, including brown adipose tissue–mediated (BAT-mediated) thermogenesis. Catecholamines also promote WAT “browning” by increasing uncoupling protein 1 (UCP1) and mitochondrial and metabolic enzymes that promote energy consumption. Dianxin Liu and colleagues identify a noncanonical pathway wherein the classical insulin signaling hub of mTORC1 and

p70 ribosomal S6 kinase 1 (S6K1) is independently activated by catecholamines through βARs and protein kinase A (PKA). Mechanistically, they determined that catecholamine-stimulated βARs and PKA directly phosphorylate serines in mTORC1 and its partner Raptor, resulting in S6K1 activation and increased UCP1 expression. Catecholamines could not stimulate adipose browning in mTORC1-deficient mice or in cells expressing a Raptor mutant that lacks PKA-specific phosphorylation sites; nevertheless, insulin-induced S6K1 activation was unaffected by this mutation. These

findings identify a catecholamine/βAR/PKA/mTORC1 signaling axis that mediates WAT browning and that may also be an important pathway in other tissues.

Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browningDianxin Liu, Marica Bordicchia, Chaoying Zhang, Huafeng Fang, Wan Wei, Jian-Liang Li, Adilson Guilherme, Kalyani Guntur, Michael P. Czech, and Sheila Collins http://jci.me/83532

neuroscience

Amyloid precursor proteins disrupt endocytosis to induce axonal dysfunction

Alzheimer’s disease (AD) and Down syndrome (Ds) are both characterized by endocytic dysfunction. The small GTPase Rab5 regulates endocytosis and intracellular trafficking, and abnormally enlarged Rab5 endosomes are observed in both AD and DS. Wei Xu and colleagues examined the interaction between Rab5 and amyloid precursor protein (APP), which accumulates in AD plaques and is overexpressed in DS. Using human and rodent models, they demonstrate that full-length APP and its C-terminal fragments (CTFs) increased levels of active, GTP-bound Rab5 (GTP-Rab5), resulting in endosomal enlargement and impaired nerve growth factor (NGF) transport. Overexpression of APP in Drosophila caused axonal blockage that was rescued by expression of a dominant negative Rab5 mutant (see the accompanying image). These studies indicate that Rab5 dysregulation contributes to AD and DS pathogenesis.

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegenerationWei Xu, April M. Weissmiller, Joseph A. White II, Fang Fang, Xinyi Wang, Yiwen Wu, Matthew L. Pearn, Xiaobei Zhao, Mariko Sawa, Shengdi Chen, Shermali Gunawardena, Jianqing Ding, William C. Mobley, and Chengbiao Wu http://jci.me/82409

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JCI | Research: Editor’s picks

A2A adenosine receptor activation boosts drug accumulation in the brain

vascular biology

the blood-brain barrier (BBB) consists of a layer of specialized endothelial cells that protects the brain from toxic substances in the peripheral circulation; however, the BBB also impedes access of therapeutic agents for neurological diseases. Using human and mouse primary endothelial cells as an in vitro BBB model, Do-Geun Kim and Margaret Bynoe demonstrate that expression of the drug efflux transporters P-glycoprotein (P-gp) and BCRP1 is reduced by activation of the A2A adenosine receptor (A2A AR). Treatment with the FDA-approved A2A AR–specific agonist Lexiscan induced rapid, reversible decreases in cell-surface expression and function of P-gp and BCRP1 via multiple pathways, including MMP9-mediated cleavage and ubiquitination. Moreover, WT mice treated with Lexiscan exhibited enhanced brain accumulation of chemotherapeutic drugs (see the accompanying image). These data indicate that A2A AR may be a suitable target for fine-tuning drug delivery to the brain.

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrierDo-Geun Kim and Margaret S. Bynoe http://jci.me/76207

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JCI | Research: Editor’s picks

immunology

CD8+ Tregs release NOX2-loaded microvesicles to suppress CD4+ T cell activationAging is associated with the loss of both protective immunity and immunosuppressive Tregs, resulting in an increased risk of immunodeficiency and chronic inflammatory disease. In this issue, Zhenke Wen, Yasuhiro Shimojima, and colleagues describe an immunoregulatory mechanism in which CD8+CCR7+ Tregs directly inhibit CD4+ T cell activation in secondary lymphoid organs by releasing microvesicles that contain NADPH oxidase 2 (NOX2) and ROS (see the accompanying image), thereby blocking T cell receptor (TCR) signaling in recipient cells by reducing phosphorylation of the TCR-associated kinase ZAP70. Importantly, CD8+ T cells from aged donors, in particular patients with the age-associated vasculitis giant cell arteritis, failed to upregulated NOX2 and were unable to prevent CD4+ T cell activation; however, this defect was rescued by NOX2 overexpression. In the accompanying Commentary, Christoph Berger and Christoph Hess discuss how these studies provide insights into the mechanisms underlying the loss of immune homeostasis with age.

NADPH oxidase deficiency underlies dysfunction of aged CD8+ TregsZhenke Wen, Yasuhiro Shimojima, Tsuyoshi Shirai, Yinyin Li, Jihang Ju, Zhen Yang, Lu Tian, Jörg J. Goronzy, and Cornelia M. Weyand http://jci.me/84181

Related CommentaryNeglected for too long? — CD8+ Tregs release NOX2-loaded vesicles to inhibit CD4+ T cellsChristoph T. Berger and Christoph Hess http://jci.me/87429

pulmonology

Neuropeptide Y enhances airway contractility and hyperresponsivenessAsthma is a complex disease that involves the immune system, airway smooth muscle, and the airway epithelium. Shanru Li and colleagues examined the molecular mechanisms in airway epithelial cells that contribute to airway hyperresponsiveness (AHR). They found that mice lacking the airway epithelial transcription factors Foxp1 and Foxp4 ectopically expressed the neurotransmitter neuropeptide Y (NPY) in the airway epithelium (see the accompanying image).

These animals exhibited greater airway resistance than control animals, which could be reversed by deletion of Npy. NPY-treated human lung airway explants exhibited increased contractility, which was mediated by enhanced Rho kinase activity and phosphorylation of myosin light chain in airway smooth muscle. These findings demonstrate that NPY-mediated paracrine signaling from the airway epithelium to the smooth muscle may play a role in asthma.

Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsivenessShanru Li, Cynthia Koziol-White, Joseph Jude, Meiqi Jiang, Hengjiang Zhao, Gaoyuan Cao, Edwin Yoo, William Jester, Michael P. Morley, Su Zhou, Yi Wang, Min Min Lu, Reynold A. Panettieri Jr., and Edward E. Morrisey http://jci.me/81389

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JCI | Features

reviews

The shelterin complex in telomere protection and hematopoiesisthe shelterin complex protects mammalian telomeres from DNA repair mechanisms and regulates telomerase activity. Telomere erosion is known to contribute to a range of human diseases, including BM failure, premature aging, and cancer. Ivan Maillard and colleagues review the function of each of the components of the shelterin complex, as well as the effect of knocking out individual components in mice. Additionally, they discuss the role of the shelterin complex in human BM–failure syndromes, including dyskeratosis congenita, a rare genetic disorder caused by mutations in genes that are important for the processing, integrity, or function of the telomerase holoenzyme. These findings point to a broader role for the shelterin complex in hematopoiesis.

The shelterin complex and hematopoiesisMorgan Jones, Kamlesh Bisht, Sharon A. Savage, Jayakrishnan Nandakumar, Catherine E. Keegan, and Ivan Maillard http://jci.me/84547

Redox systems in cancer and HIVReactive oxygen and nitrogen species (Ros and Rns) influence a broad spectrum of physiological and pathophysiological processes. Antioxidants have been proposed as a treatment for cancer and HIV for several decades; however, recent studies have indicated that antioxidants may not be beneficial in these diseases. Andrea Savarino and colleagues review the role of the thioredoxin (Trx) and glutathione (GSH) systems in cancer and HIV. Dual inhibition of these systems synergistically kills neoplastic cells and enhances their sensitivity to anticancer therapeutics. Additionally, cells that harbor proviral HIV also appear to be sensitive to Trx and GSH inhibitors. Thus, decreasing cellular defenses against ROS and RNS may be a viable strategy for the treatment of cancer and HIV, and further studies will be necessary to establish the exact role of these systems in specific disease subtypes and mechanisms.

Dual targeting of the thioredoxin and glutathione systems in cancer and HIVMoran Benhar, Iart Luca Shytaj, Jonathan S. Stamler, and Andrea Savarino http://jci.me/85339

Determining the role of neutrophil extracellular trapsneutrophil extracellular traps (nets) are extracellular strands of decondensed DNA complexed with histones and granule proteins that are released from neutrophils. NETs are reported to play a role in pathogen elimina-tion; however, it is unclear whether this is their predominant function, as NETs may also spur autoantibody formation and serve as a scaffold for thrombosis. Ole Sørenson and Niels Borregaard review the mechanisms underlying NET formation and discuss the physiological and pathophysiological consequences of NET formation and discrepancies between in vitro and in vivo studies. They conclude that NETs are generated in response to local infection, but that they do not play a major role in host defense. Instead, NETs appear to be important in thrombosis, vasculitis, and autoimmune diseases (see the accompanying image).

Neutrophil extracellular traps — the dark side of neutrophilsOle E. Sørensen and Niels Borregaard http://jci.me/84538

conversations with giants in medicine

Bert Vogelstein and Ken KinzlerBert Vogelstein, MD, and Kenneth Kinzler, PhD, are codirectors of the Ludwig Center at the Sidney Kimmel Comprehensive Cancer Center of the Johns Hopkins University School of Medicine. Vogelstein and Kinzler demonstrated that colorectal cancer results from the sequential accumulation of mutations in oncogenes and tumor suppressor genes, establishing a paradigm for modern cancer genomics.

Additionally, they discovered the tumor suppressors APC and TP53; they were the first to perform exomic sequencing in tumors; and they developed digital PCR. In an interview with JCI’s Editor-at-Large Ushma Neill, Vogelstein and Kinzler reflect on their career trajectories and past discoveries and discuss their goals as scientists. http://jci.me/86754

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bone biologyHedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis p. 2Jason S. Rockel, Chunying Yu, Heather Whetstone, April M. Craft, Katherine Reilly, Henry Ma, Hidetoshi Tsushima, Vijitha Puviindran, Mushriq Al-Jazrawe, Gordon M. Keller, and Bejamin A. Alman http://jci.me/80205

Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model p. 1Davide Komla-Ebri, Emilie Dambroise, Ina Kramer, Catherine Benoist-Lasselin, Nabil Kaci, Cindy Le Gall, Ludovic Martin, Patricia Busca, Florent Barbault, Diana Graus-Porta, Arnold Munnich, Michaela Kneissel, Federico Di Rocco, Martin Biosse-Duplan, and Laurence Legeai-Mallet http://jci.me/83926

development4-Dimensional light-sheet microscopy to elucidate shear stress modulation of cardiac trabeculationJuhyun Lee, Peng Fei, René R. Sevag Packard, Hanul Kang, Hao Xu, Kyung In Baek, Nelson Jen, Junjie Chen, Hilary Yen, C.-C. Jay Kuo, Neil C. Chi, Chih-Ming Ho, Rongsong Li, and Tzung K. Hsiai http://jci.me/83496

endocrinologyActivation of mTORC1 is essential for β-adrenergic stimulation of adipose browning p. 4Dianxin Liu, Marica Bordicchia, Chaoying Zhang, Huafeng Fang, Wan Wei, Jian-Liang Li, Adilson Guilherme, Kalyani Guntur, Michael P. Czech, and Sheila Collins http://jci.me/83532

Stress-impaired transcription factor expression and insulin secretion in transplanted human isletsChunhua Dai, Nora S. Kayton, Alena Shostak, Greg Poffenberger, Holly A. Cyphert, Radhika Aramandla, Courtney Thompson, Ioannis G. Papagiannis, Christopher Emfinger, Masakazu Shiota, John M. Stafford, Dale L. Greiner, Pedro L. Herrera, Leonard D. Shultz, Roland Stein, and Alvin C. Powers http://jci.me/83657

hematologyEvaluation of direct-to-consumer low-volume lab tests in healthy adultsBrian A. Kidd, Gabriel Hoffman, Noah Zimmerman, Li Li, Joseph W. Morgan, Patricia K. Glowe, Gregory J. Botwin, Samir Parekh, Nikolina Babic, Matthew W. Doust, Gregory B. Stock, Eric E. Schadt, and Joel T. Dudley http://jci.me/86318

immunologyNLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22Marianne R. Spalinger, Stephanie Kasper, Claudia Gottier, Silvia Lang, Kirstin Atrott, Stephan R. Vavricka, Sylvie Scharl, Petrus M. Gutte, Markus G. Grütter, Hans-Dietmar Beer, Emmanuel Contassot, Andrew C. Chan, Xuezhi Dai, David J. Rawlings, Florian Mair, Burkhard Becher, Werner Falk, Michael Fried, Gerhard Rogler, and Michael Scharl http://jci.me/83669

NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs p. 6Zhenke Wen, Yasuhiro Shimojima, Tsuyoshi Shirai, Yinyin Li, Jihang Ju, Zhen Yang, Lu Tian, Jörg J. Goronzy, and Cornelia M. Weyand http://jci.me/84181

Dendritic cell dysfunction and diabetic sensory neuropathy in the corneaNan Gao, Chenxi Yan, Patrick Lee, Haijing Sun, and Fu-Shin Yu http://jci.me/85097

Current research articles

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metabolismHypomorphism of Fto and Rpgrip1l causes obesity in miceGeorge Stratigopoulos, Lisa Cole Burnett, Richard Rausch, Richard Gill, David Barth Penn, Alicja A. Skowronski, Charles A. LeDuc, Anthony J. Lanzano, Pumin Zhang, Daniel R. Storm, Dieter Egli, and Rudolph L. Leibel http://jci.me/85526

nephrologyCollectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injuryConrad A. Farrar, David Tran, Ke Li, Weiju Wu, Qi Peng, Wilhelm Schwaeble, Wuding Zhou, and Steven H. Sacks http://jci.me/83000

mTORC2 critically regulates renal potassium handling p. 3Florian Grahammer, Viatcheslav Nesterov, Azaz Ahmed, Frederic Steinhardt, Lukas Sandner, Frederic Arnold, Tomke Cordts, Silvio Negrea, Marko Bertog, Marcus A. Ruegg, Michael N. Hall, Gerd Walz, Christoph Korbmacher, Ferruh Artunc, and Tobias B. Huber http://jci.me/80304

Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietinHanako Kobayashi, Qingdu Liu, Thomas C. Binns, Andres A. Urrutia, Olena Davidoff, Pinelopi P. Kapitsinou, Andrew S. Pfaff, Hannes Olauson, Annika Wernerson, Agnes B. Fogo, Guo-Hua Fong, Kenneth W. Gross, and Volker H. Haase http://jci.me/83551

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes p. 3Tsuyoshi Inoue, Chikara Abe, Sun-sang J. Sung, Stefan Moscalu, Jakub Jankowski, Liping Huang, Hong Ye, Diane L. Rosin, Patrice G. Guyenet, and Mark D. Okusa http://jci.me/83658

Improved renal ischemia tolerance in females influences kidney transplantation outcomes p. 3David D. Aufhauser Jr., Zhonglin Wang, Douglas R. Murken, Tricia R. Bhatti, Yanfeng Wang, Guanghui Ge, Robert R. Redfield III, Peter L. Abt, Liqing Wang, Nikolaos Svoronos, Arwin Thomasson, Peter P. Reese, Wayne W. Hancock, and Matthew H. Levine http://jci.me/84712

neuroscienceAmyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration p. 4Wei Xu, April M. Weissmiller, Joseph A. White II, Fang Fang, Xinyi Wang, Yiwen Wu, Matthew L. Pearn, Xiaobei Zhao, Mariko Sawa, Shengdi Chen, Shermali Gunawardena, Jianqing Ding, William C. Mobley, and Chengbiao Wu http://jci.me/82409

Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic painSun Kwang Kim, Hideaki Hayashi, Tatsuya Ishikawa, Keisuke Shibata, Eiji Shigetomi, Youichi Shinozaki, Hiroyuki Inada, Seung Eon Roh, Sang Jeong Kim, Gihyun Lee, Hyunsu Bae, Andrew J. Moorhouse, Katsuhiko Mikoshiba, Yugo Fukazawa, Schuichi Koizumi, and Junichi Nabekura http://jci.me/82859

Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis modelKeisuke Kitakaze, Yasumichi Mizutani, Eiji Sugiyama, Chikako Tasaki, Daisuke Tsuji, Nobuo Maita, Takatsugu Hirokawa, Daisuke Asanuma, Mako Kamiya, Kohei Sato, Mitsutoshi Setou, Yasuteru Urano, Tadayasu Togawa, Akira Otaka, Hitoshi Sakuraba, and Kohji Itoh http://jci.me/85300

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JCI | Current research articles

oncologySOX9 drives WNT pathway activation in prostate cancerFen Ma, Huihui Ye, Housheng Hansen He, Sean J. Gerrin, Sen Chen, Benjamin A. Tanenbaum, Changmeng Cai, Adam G. Sowalsky, Lingfeng He, Hongyun Wang, Steven P. Balk, and Xin Yuan http://jci.me/78815

Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic diseaseJing Fu, Shirong Li, Rentian Feng, Huihui Ma, Farideh Sabeh, G. David Roodman, Ji Wang, Samuel Robinson, X. Edward Guo, Thomas Lund, Daniel Normolle, Markus Y. Mapara, Stephen J. Weiss, and Suzanne Lentzsch http://jci.me/80276

MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesisTakashi Yokoyama, Mayuka Nakatake, Takeshi Kuwata, Arnaud Couzinet, Ryo Goitsuka, Shuichi Tsutsumi, Hiroyuki Aburatani, Peter J.M. Valk, Ruud Delwel, and Takuro Nakamura http://jci.me/81516

Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitorsGao Zhang, Dennie T. Frederick, Lawrence Wu, Zhi Wei, Clemens Krepler, Satish Srinivasan, Young Chan Chae, Xiaowei Xu, Harry Choi, Elaida Dimwamwa, Omotayo Ope, Batool Shannan, Devraj Basu, Dongmei Zhang, Manti Guha, Min Xiao, Sergio Randell, Katrin Sproesser, Wei Xu, Jephrey Liu, Giorgos C. Karakousis, Lynn M. Schuchter, Tara C. Gangadhar, Ravi K. Amaravadi, Mengnan Gu, Caiyue Xu, Abheek Ghosh, Weiting Xu, Tian Tian, Jie Zhang, Shijie Zha, Qin Liu, Patricia Brafford, Ashani Weeraratna, Michael A. Davies, Jennifer A. Wargo, Narayan G. Avadhani, Yiling Lu, Gordon B. Mills, Dario C. Altieri, Keith T. Flaherty, and Meenhard Herlyn http://jci.me/82661

c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastomaMenggui Huang, Tianrun Liu, Peihong Ma, R. Alan Mitteer Jr., Zhenting Zhang, Hyun Jun Kim, Eujin Yeo, Duo Zhang, Peiqiang Cai, Chunsheng Li, Lin Zhang, Botao Zhao, Laura Roccograndi, Donald M. O’Rourke, Nadia Dahmane, Yanqing Gong, Constantinos Koumenis, and Yi Fan http://jci.me/84876

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal p. 2Monika Haemmerle, Justin Bottsford-Miller, Sunila Pradeep, Morgan L. Taylor, Hyun-Jin Choi, Jean M. Hansen, Heather J. Dalton, Rebecca L. Stone, Min Soon Cho, Alpa M. Nick, Archana S. Nagaraja, Tony Gutschner, Kshipra M. Gharpure, Lingegowda S. Mangala, Rajesha Rupaimoole, Hee Dong Han, Behrouz Zand, Guillermo N. Armaiz-Pena, Sherry Y. Wu, Chad V. Pecot, Alan R. Burns, Gabriel Lopez-Berestein, Vahid Afshar-Kharghan, and Anil K. Sood http://jci.me/85086

pulmonologyEpithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness p. 6Shanru Li, Cynthia Koziol-White, Joseph Jude, Meiqi Jiang, Hengjiang Zhao, Gaoyuan Cao, Edwin Yoo, William Jester, Michael P. Morley, Su Zhou, Yi Wang, Min Min Lu, Reynold A. Panettieri Jr., and Edward E. Morrisey http://jci.me/81389

vascular biologyA2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier p. 5Do-Geun Kim and Margaret S. Bynoe http://jci.me/76207

j c i . o r g / t h i s - m o n t h m a y 2 0 1 6 11

JCI Insight is a new peer-reviewed journal dedicated to biomedical research, ranging from preclinical to clinical studies.More information: http://jci.me/insinf or editors@insight.jci.org

pulmonology

Intranasal vaccinia vaccine–based immunotherapy ameliorates pulmonary fibrosisidiopathic pulmonary fibrosis (iPF) is a fatal condition characterized by dysregulated wound healing and unregulated fibrosis, along with low-grade, chronic T cell infiltration, indicating that T cells may play a role in pathogenesis. Using a murine model of established lung fibrosis, Samuel Collins and colleagues demonstrated that intranasal administration of a vaccinia vaccine induced an antifibrotic T cell response that arrested and reversed lung fibrosis, including decreases in fibrocyte recruitment and collagen deposition (see the accompanying image) and improved lung function. Analysis of treated lungs revealed that vaccinia vaccination created a lung niche for IFNG-producing CD4+ T resident memory cells (Trm), which were required for reversal of the pathology. Additionally, Collins and colleagues observed a vaccine-induced decrease in Th17 cells and CXCL12, which have been implicated in fibrosis. These data indicate that immunotherapy to modulate Trm is a potential therapeutic strategy for pathologies characterized by inflammation and fibrosis.

Vaccinia vaccine–based immunotherapy arrests and reverses established pulmonary fibrosisSamuel L. Collins, Yee Chan-Li, MinHee Oh, Christine L. Vigeland, Nathachit Limjunyawong, Wayne Mitzner, Jonathan D. Powell, and Maureen R. Horton http://jci.me/83116

Pleiotropic effects of IL-1β in pancreatic islet function

metabolism

the inflammatory cytokine il-1β has been implicated in β cell dysfunction in the setting of type 2 diabetes (T2D), but clinical trials of IL-1 inhibition have had conflicting results. Catherine Hajmrle and colleagues demonstrated that islets from obese donors were sensitized to IL-1β and exhibited enhanced potentiation of glucose-stimulated insulin secretion, while islets from T2D donors were insensitive to this effect of IL-1β. Using murine islets, Hajmrle and colleagues showed that acute treatment with IL-1β enhances insulin secretion by increasing insulin granule docking (see the accompanying image). Mice lacking the type 1 IL-1 receptor exhibited impaired insulin secretion and became glucose intolerant more rapidly than WT mice in response to a high-fat diet or acute LPS injection. These data demonstrate a role for IL-1 signaling in islet compensatory responses to metabolic stress and may explain the conflicting results of IL-1 inhibitors in clinical trials.

Interleukin-1 signaling contributes to acute islet compensationCatherine Hajmrle, Nancy Smith, Aliya F. Spigelman, Xiaoqing Dai, Laura Senior, Austin Bautista, Mourad Ferdaoussi, and Patrick E. MacDonald http://jci.me/86055

Editor’s picks

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Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in miceSamit Ghosh, Chibueze A. Ihunnah, Rimi Hazra, Aisha L. Walker, Jason M. Hansen, David R. Archer, Amma T. Owusu-Ansah, and Solomon F. Ofori-Acquah http://jci.me/81090

Vaccinia vaccine–based immunotherapy arrests and reverses established pulmonary fibrosis p. 11Samuel L. Collins, Yee Chan-Li, MinHee Oh, Christine L. Vigeland, Nathachit Limjunyawong, Wayne Mitzner, Jonathan D. Powell, and Maureen R. Horton http://jci.me/83116

NFAT restricts osteochondroma formation from entheseal progenitorsXianpeng Ge, Kelly Tsang, Lizhi He, Roberto A. Garcia, Joerg Ermann, Fumitaka Mizoguchi, Minjie Zhang, Bin Zhou, Bin Zhou, and Antonios O. Aliprantis http://jci.me/86254

Interleukin-1 signaling contributes to acute islet compensation p. 11Catherine Hajmrle, Nancy Smith, Aliya F. Spigelman, Xiaoqing Dai, Laura Senior, Austin Bautista, Mourad Ferdaoussi, and Patrick E. MacDonald http://jci.me/86055

Functional significance of the discordance between transcriptional profile and left ventricular structure/function during reverse remodelingVeli K. Topkara, Kari T. Chambers, Kai-Chien Yang, Huei-Ping Tzeng, Sarah Evans, Carla Weinheimer, Attila Kovacs, Jeffrey Robbins, Philip Barger, and Douglas L. Mann http://jci.me/86038

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalitiesRyan J. Adam, Katherine B. Hisert, Jonathan D. Dodd, Brenda Grogan, Janice L. Launspach, Janel K. Barnes, Charles G. Gallagher, Jered P. Sieren, Thomas J. Gross, Anthony J. Fischer, Joseph E. Cavanaugh, Eric A. Hoffman, Pradeep K. Singh, Michael J. Welsh, Edward F. McKone, and David A. Stoltz http://jci.me/86183

Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALLMichelle L. Churchman, Kathryn Evans, Jennifer Richmond, Alissa Robbins, Luke Jones, Irina M. Shapiro, Jonathan A. Pachter, David T. Weaver, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, and Charles G. Mullighan http://jci.me/86082

Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6–deficient processPiers E.M. Patten, Gerardo Ferrer, Shih-Shih Chen, Rita Simone, Sonia Marsilio, Xiao-Jie Yan, Zachary Gitto, Chaohui Yuan, Jonathan E. Kolitz, Jacqueline Barrientos, Steven L. Allen, Kanti R. Rai, Thomas MacCarthy, Charles C. Chu, and Nicholas Chiorazzi http://jci.me/86288

Eosinophilic esophagitis–linked calpain 14 is an IL-13–induced protease that mediates esophageal epithelial barrier impairmentBenjamin P. Davis, Emily M. Stucke, M. Eyad Khorki, Vladislav A. Litosh, Jeffrey K. Rymer, Mark Rochman, Jared Travers, Leah C. Kottyan, and Marc E. Rothenberg http://jci.me/86355

Sickle cell–associated lung injury

Nfatc1-deficient hip joint

Air trapping regions

B cell aggregates

Current research articles

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Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myelomaYoichi Imai, Eri Ohta, Shu Takeda, Satoko Sunamura, Mariko Ishibashi, Hideto Tamura, Yan-hua Wang, Atsuko Deguchi, Junji Tanaka, Yoshiro Maru, and Toshiko Motoji http://jci.me/85061

Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle massJonathan R. Davey, Kevin I. Watt, Benjamin L. Parker, Rima Chaudhuri, James G. Ryall, Louise Cunningham, Hongwei Qian, Vittorio Sartorelli, Marco Sandri, Jeffrey Chamberlain, David E. James, and Paul Gregorevic http://jci.me/85477

Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritisLucy V. Norling, Sarah E. Headland, Jesmond Dalli, Hildur H. Arnardottir, Oliver Haworth, Hefin R. Jones, Daniel Irimia, Charles N. Serhan, and Mauro Perretti http://jci.me/85922

Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathyStephen P. Chelko, Angeliki Asimaki, Peter Andersen, Djahida Bedja, Nuria Amat-Alarcon, Deeptankar DeMazumder, Ravirasmi Jasti, Calum A. MacRae, Remo Leber, Andre G. Kleber, Jeffrey E. Saffitz, and Daniel P. Judge http://jci.me/85923

PD-1 marks dysfunctional regulatory T cells in malignant gliomasDaniel E. Lowther, Brittany A. Goods, Liliana E. Lucca, Benjamin A. Lerner, Khadir Raddassi, David van Dijk, Amanda L. Hernandez, Xiangguo Duan, Murat Gunel, Vlad Coric, Smita Krishnaswamy, J. Christopher Love, and David A. Hafler http://jci.me/85935

Three-dimensional characterization of fibroblast foci in idiopathic pulmonary fibrosisMark G. Jones, Aurélie Fabre, Philipp Schneider, Francesco Cinetto, Giacomo Sgalla, Mark Mavrogordato, Sanjay Jogai, Aiman Alzetani, Ben G. Marshall, Katherine M.A. O’Reilly, Jane A. Warner, Peter M. Lackie, Donna E. Davies, David M. Hansell, Andrew G. Nicholson, Ian Sinclair, Kevin K. Brown, and Luca Richeldi http://jci.me/86375

Mst1-mediated phosphorylation of Bcl-xL is required for myocardial reperfusion injuryMichinari Nakamura, Peiyong Zhai, Dominic P. Del Re, Yasuhiro Maejima, and Junichi Sadoshima http://jci.me/86217

Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamideChristopher G. Kanakry, David G. Coffey, Andrea M.H. Towlerton, Ante Vulic, Barry E. Storer, Jeffrey Chou, Cecilia C.S. Yeung, Christopher D. Gocke, Harlan S. Robins, Paul V. O’Donnell, Leo Luznik, and Edus H. Warren http://jci.me/86252

Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overloadYi Zhang, Yan Huang, Anna Cantalupo, Paula S. Azevedo, Mauro Siragusa, Jacek Bielawski, Frank J. Giordano, and Annarita Di Lorenzo http://jci.me/85484

Multiple myeloma caspase-3

Cardiac fibrosis

Ventricular myocytes

3D rendering of lung

Christopher M. Adams

Maria-Luisa Alegre

Ravi K. Amaravadi

John K. Amory

Jennifer H. Anolik

Cristian Apetrei

Rajendra S. Apte

Zoltan Arany

Hossein Ardehali

Kenneth I. Ataga

Joseph Bass

Alexander G. Bassuk

Antonio C. Bianco

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

Sebastien G. Bouret

Jason Brenchley

Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

Stephen Chan

Yuan Chang

Zhou-Feng Chen

Keith A. Choate

Wendy Chung

Craig M. Coopersmith

George Cotsarelis

Peter Crawford

Lisa L. Cunningham

Ronald P. DeMatteo

Elia J. Duh

Sarah K. England

Mark W. Feinberg

John H. Fingert

Robert Flaumenhaft

Edward A. Fon

Lawrence Fong

Nikolaos G. Frangogiannis

Anthony R. French

Terrence L. Geiger

Noyan Gokce

Raphaela Goldbach-Mansky

Daniel R. Goldstein

Douglas K. Graham

Khalid A. Hanafy

Eric B. Haura

John Cijiang He

Robert O. Heuckeroth

Cory M. Hogaboam

Young-Kwon Hong

Benjamin D. Humphreys

Ken Inoki

Shingo Kajimura

Pawel Kalinski

John Y. Kao

Mariana J. Kaplan

Michael G. Kaplitt

Barbara I. Kazmierczak

Hans-Peter Kiem

William Y. Kim

David G. Kirsch

Mathias Lichterfeld

André Lieber

Michail S. Lionakis

Carey N. Lumeng

Leo Luznik

Ivan Maillard

Ziad Mallat

Peter Mannon

Franck Mauvais-Jarvis

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

Jason C. Mills

Joshua D. Milner

Satdarshan (Paul) Singh Monga

Hidayatullah G. Munshi

Matthias Nahrendorf

Mary Nakamura

Lisa F.P. Ng

Mark Nicolls

Laura J. Niedernhofer

Deborah V. Novack

S. Tiong Ong

Puneet Opal

Daniel Ory

Sophie Paczesny

Stephanie T. Page

Mary-Elizabeth Patti

Janos Peti-Peterdi

Fernando P. Polack

Matthew D. Ringel

Steven M. Rowe

Svati H. Shah

Vijay H. Shah

Alice T. Shaw

Rhonda F. Souza

Fayyaz S. Sutterwala

Shu Takeda

Natalie J. Torok

Stephen H. Tsang

Ellie Tzima

Mark C. Udey

Fumihiko Urano

Charles P. Venditti

Joseph M. Vinetz

Sing Sing Way

Bernd Wollnik

Minna Woo

Prescott G. Woodruff

Lori M. Zeltser

Yutong Zhao

Binhua P. Zhou

JCI Insight Consulting Editors