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ALSO IN THIS ISSUE:

Prolyl hydroxylase 2 calibrates neutrophil function and timing 2

Coordinating maturity and function in neural stem cell transplants 3

Treg depletion enhances breast cancer immunotherapy 4

Review Series: Glia and neurodegeneration edited by Marco Colonna and David Holtzmann 6

JCI Insight 10

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September 2017

Differential requirements for TNF in allergic inflammation p. 1

This Month

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This MonthSeptember 2017

Immune responses differentially involve TNF signaling in allergic airway inflammation

On the JCI cover

Allergic asthma is often regarded as a dis-ease of eosinophilic airway inflammation, but over half of asthmatic patients display predominant neutrophilia. Those patients are frequently refractory to frontline steroid treatments, underscoring a need for more effective and targeted thera-pies. Clinical trials have shown that TNF antagonists are effective in some patients but not others, suggesting that TNF might only be required in some forms of asthma. The heterogeneity in asthma might be related to the diversity of allergens and adjuvants and the innate immune respons-es that they activate. In this issue of the

JCI, Whitehead et al. dissect the inflammatory pathways and immune responses evoked in TLR ligand–sensitized and protease-sensitized airways. Mice sensi-tized by inhaling an allergen together with TLR ligands developed eosinophilia and neutrophils following subsequent allergen challenge, whereas protease-mediated sensitization predominantly evoked eosinophilic inflammation. TLR ligand–mediated sensitization induced TNF signaling in airway epithelial cells and was associated with the differentiation of Th2 cells, but not Th17 cells. TNF also acted during the challenge phase, promoting Th17 cell, eosinophil, and neutrophil recruitment to the airway in TLR ligand–sensitized, but not protease-sensitized, mice. These findings might help to explain the variable efficacy of TNF antagonists in clinical trials. Further, the observations lay the groundwork for investigating allergen-specific immune pathways and personalized therapies for allergic asthma. On this issue’s cover, a section of mouse lung shows CD11c+ DCs (green) and Th17 fate-mapping cells (red) adjacent to E-cadherin+ airways and alveoli (blue). Image credit: Miranda Lyons-Cohen.

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammationGregory S. Whitehead, Seddon Y. Thomas, Karim H. Shalaby, Keiko Nakano, Timothy P. Moran, James M. Ward, Gordon P. Flake, Hideki Nakano, and Donald N. Cook http://jci.me/90890

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.

j c i . o r g / t h i s - m o n t h s e p t e m b e r 2 0 1 72

research

Editor’s picks

immunology

Prolyl hydroxylase 2 expression limits activated neutrophil life span and functionDuring the acute phase of inflammation, activated neutrophils are rapidly recruited to sites of infection, where they release cytokines that intensify the inflammatory response. Mechanisms that restrict the duration of neutrophil responses are important for limiting tissue damage that results from long-lasting inflammation. Pranvera Sadiku and coworkers examined the role of the prolyl hydroxylase PHD2, which targets HIFs for degradation, in regulating the survival and function of activated neutrophils. They found that myeloid-specific PHD2 deficiency enhanced neutrophil responses, leading to exaggerated inflammatory responses and lung injury in Streptococcus pneumonia–infected mice. The increased function and survival of PHD2-deficient neutrophils were driven by boosts in glycolytic metabolism. These findings identify PHD2 as a critical regulator of neutrophil-mediated inflammatory responses as well as neutrophil metabolism, suggesting that it may be an important target in the treatment of inflammatory disease.

Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responsesPranvera Sadiku, Joseph A. Willson, Rebecca S. Dickinson, Fiona Murphy, Alison J. Harris, Amy Lewis, David Sammut, Ananda S. Mirchandani, Eilise Ryan, Emily R. Watts, A.A. Roger Thompson, Helen M. Marriott, David H. Dockrell, Cormac T. Taylor, Martin Schneider, Patrick H. Maxwell, Edwin R. Chilvers, Massimilliano Mazzone, Veronica Moral, Chris W. Pugh, Peter J. Ratcliffe, Christopher J. Schofield, Bart Ghesquiere, Peter Carmeliet, Moira K.B. Whyte, and Sarah R. Walmsley http://jci.me/90848

NBEAL2 mutations impair neutrophil- and NK cell–mediated pathogen defensePlatelet abnormalities and bleeding tendency in gray platelet syndrome (GPS) are linked to mutations in the scaffolding protein neurobeachin-like 2 (NBEAL2). Some patients with GPS also have increased susceptibility to infection, but the effects of NBEAL mutations on other cells of the hematopoetic cell lineage are unknown. John Sowerby and colleagues evaluated the phenotype of NBEAL2-deficient mice and observed marked impairments in neutrophil and NK cell function. Neutrophils in NBEAL2-deficient mice lacked multiple granule subsets (see the accompanying image), which increased their susceptibility to Staphylococcus aureus infection. Loss of NBEAL2 also compromised degranulation in NK cells, resulting in profound defects in antiviral immunity. Further investigation of the contribution of NBEAL2 to immune function may reveal mechanisms and pathways underlying immunodeficiency in GPS and other disorders.

NBEAL2 is required for neutrophil and NK cell function and pathogen defenseJohn M. Sowerby, David C. Thomas, Simon Clare, Marion Espéli, Jose A. Guerrero, Kim Hoenderdos, Katherine Harcourt, Morgan Marsden, Juneid Abdul-Karim, Mathew Clement, Robin Antrobus, Yagnesh Umrania, Philippa R. Barton, Shaun M. Flint, Jatinder K. Juss, Alison M. Condliffe, Paul A. Lyons, Ian R. Humphreys, Edwin R. Chilvers, Willem H. Ouwehand, Gordon Dougan, and Kenneth G.C. Smith http://jci.me/91684

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JCI | Research: Editor’s picks

neuroscience

5-HT 2C receptors contribute to metabolic side effects of atypical antipsychoticsAtypical antipsychotics target multiple monoaminergic receptors in the brain, but their therapeutic effect on psychiatric disorders is believed to result from combined blockade of serotonin 5-HT 2A and dopamine D2 receptors. Despite their efficacy, several atypical antipsychotics have undesirable side effects that drive obesity and type 2 diabetes. Caleb Lord and colleagues investigated the mechanisms underlying excessive weight gain linked to atypical antipsychotics in olanzapine-treated mice. Olanzapine treatment led to hyperphagia, impaired glucose tolerance, and reductions in physical activity and energy expenditure. These increases in feeding and weight gain were blunted in 5-HT 2C receptor–deficient mice as well as mice cotreated with the 5-HT 2C agonist lorcaserin. Cotreatment with lorcaserin also led to improvements in glucose homeosta-sis, suggesting that selective targeting of 5-HT 2C receptors may ameliorate the metabolic effects of atypical antipsychotics.

The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2CCaleb C. Lord, Steven C. Wyler, Rong Wan, Carlos M. Castorena, Newaz Ahmed, Dias Mathew, Syann Lee, Chen Liu, and Joel K. Elmquist http://jci.me/93362

Transplanted neural stem cell maturation coincides with delayed functional improvements

EGFR signaling in sensory neurons contributes to pain processingThe therapeutic options for patients with chronic pain are limited, and many carry the risk of addiction and undesirable side effects. While several case reports describe pain relief in cancer patients undergoing treatment with EGFR- targeting agents, the analgesic properties of EGFR inhibition have not been evaluated. Loren Martin and colleagues found that epiregulin-mediated activation of EGFR enhanced nociception in mouse models of inflammatory and chronic pain. In contrast, inhibiting EGFR at the tyrosine kinase site reduced pain sensitivity in these models. Sensory neurons of the dorsal root ganglion expressed EGFR abundantly (see the accompanying image), and EGFR expression was increased in mouse models of chronic pain. Moreover, an analysis of three human cohorts linked the epiregulin/EGFR pathway to chronic pain. The identification of EGFR as a potential analgesic target may aid in the development of improved therapies for managing chronic pain.

Epiregulin and EGFR interactions are involved in pain processingLoren J. Martin, Shad B. Smith, Arkady Khoutorsky, Claire A. Magnussen, Alexander Samoshkin, Robert E. Sorge, Chulmin Cho, Noosha Yosefpour, Sivaani Sivaselvachandran, Sarasa Tohyama, Tiffany Cole, Thang M. Khuong, Ellen Mir, Dustin G. Gibson, Jeffrey S. Wieskopf, Susana G. Sotocinal, Jean Sebastien Austin, Carolina B. Meloto, Joseph H. Gitt, Christos Gkogkas, Nahum Sonenberg, Joel D. Greenspan, Roger B. Fillingim, Richard Ohrbach, Gary D. Slade, Charles Knott, Ronald Dubner, Andrea G. Nackley, Alfredo Ribeiro-da-Silva, G. Gregory Neely, William Maixner, Dmitri V. Zaykin, Jeffrey S. Mogil, and Luda Diatchenko http://jci.me/87406

Preclinical studies have demonstrated axonal extension, synapse formation, and functional improvements following implantation of human neural stem cells (NSCs) into rodent models of spinal cord injury. However, whether implanted NSCs maintain human rates of maturation or adopt an accelerated rate of development in their rodent hosts is not known. Paul Lu and coworkers assessed the maturation of human NSCs implanted into a rat model to determine the expected time course for

functional recovery. They observed that the implanted NSCs reached maturity gradually over a 12- to 18-month period, resembling the intrinsic timeline of human NSC maturation. The 12- to 18-month delay in neuronal maturation correspond-ed to similar delays in the recovery of motor function. In the accompanying Commentary, Steven Goldman discusses how these findings may influence the planning of clinical trials evaluating the functional outcomes of NSC transplantation.

Prolonged human neural stem cell maturation supports recovery in injured rodent CNSPaul Lu, Steven Ceto, Yaozhi Wang, Lori Graham, Di Wu, Hiromi Kumamaru, Eileen Staufenberg, and Mark H. Tuszynski http://jci.me/92955

Related CommentaryPatience pays in spinal repairSteven A. Goldman http://jci.me/96650

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JCI | Research: Editor’s picks

oncology GATA4 haploinsufficiency in liver cancer impairs the hepatocyte differentiation programChromosome 8 (8p) deletion is the most common chromosomal structural loss in hepatocellular carcinoma (HCC), but the key genes responsible for tumor development resulting from 8p deletion are unknown. In an analysis of commonly deleted 8p segments, Francis Enane, Wai Ho Shuen, and coworkers identified the master transcription factor GATA4 as a possible tumor-suppressor gene in HCC. In a mouse model, liver-specific Gata4 haploinsufficiency led to liver enlargement, proliferation of hepatocyte precursors, and impaired hepatocyte differentiation. Enrichment of precursor genes and suppression of hepatocyte differentiation genes in Gata4-haploinsufficient mice resembled gene expression patterns in human HCC. Moreover, HCC livers with intact 8p harbored mutations that disrupted GATA4’s interactions with coactivators, and restoring these interactions in HCC cells normalized the expression of precursor and hepatocyte gene programs. Together, these findings indicate that GATA4 loss of function is a critical driver of HCC transformation.

GATA4 loss of function in liver cancer impedes precursor to hepatocyte transitionFrancis O. Enane, Wai Ho Shuen, Xiaorong Gu, Ebrahem Quteba, Bartlomiej Przychodzen, Hideki Makishima, Juraj Bodo, Joanna Ng, Chit Lai Chee, Rebecca Ba, Lip Seng Koh, Janice Lim, Rachael Cheong, Marissa Teo, Zhenbo Hu, Kwok Peng Ng, Jaroslaw Maciejewski, Tomas Radivoyevitch, Alexander Chung, London Lucien Ooi, Yu Meng Tan, Peng-Chung Cheow, Pierce Chow, Chung Yip Chan, Kiat Hon Lim, Lisa Yerian, Eric Hsi, Han Chong Toh, and Yogen Saunthararajah http://jci.me/93488

Inhibiting Treg infiltration to claudin-low tumors improves checkpoint blockade outcomesThe claudin-low subtype of breast cancer is defined by increased expression of genes linked to adaptive and innate immunity. Claudin-low tumors also exhibit high levels of immune infiltration, and the subtype is linked to worse clinical outcomes. Nicholas Taylor, Sarah Vick, and colleagues investigated the role of tumor-infiltrating leukocytes (TILs) in the response to immune checkpoint blockade in a mouse model of claudin-low breast cancer (claudin-low mice). In spite of increased immune infiltration, checkpoint inhibition did not reduce tumor growth in claudin-low mice. A large proportion of TILs in claudin-low tumors were immunosuppressive Tregs, which were recruited by the chemokine CXCL12 and suppressed effector T cell antitumor responses. Depleting Tregs in claudin-low mice increased the efficacy of immune checkpoint blockade against tumors, indicating that interfering with Treg recruitment in claudin-low breast cancer may be a strategy for improving patient prognosis.

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancerNicholas A. Taylor, Sarah C. Vick, Michael D. Iglesia, W. June Brickey, Bentley R. Midkiff, Karen P. McKinnon, Shannon Reisdorf, Carey K. Anders, Lisa A. Carey, Joel S. Parker, Charles M. Perou, Benjamin G. Vincent, and Jonathan S. Serody http://jci.me/90499

Parathyroid hormone therapy promotes differentiation to the osteoblast lineage

bone biology

Osteoporosis reflects imbalance between the activity of bone-degrading osteoclasts and bone-building osteoblasts. Teriparatide, a recombinant form of parathyroid hormone (PTH 1–34), is currently the only approved treatment that targets bone formation in osteoporosis. Teriparatide increases the existing osteoblast population by suppressing apoptosis and activating dormant cells, but whether it also stimulates the differentiation of new osteo-blasts is unknown. Using a lineage-tracing strategy, Deepak Balani and colleagues observed

that the number of osteoblast precursors and their mature descendants increased in mice undergoing teriparatide treatment. Teriparatide-induced increases in osteoblast differentiation required expression of the PTH receptor in osteoprogenitors. Unexpectedly, withdrawal from teriparatide treatment led to an increase in adipocyte differentiation (see the accompa-nying image), suggesting that therapies targeting the PTH receptor may enhance osteoblast populations by suppressing adipocyte fates.

Parathyroid hormone regulates fates of murine osteoblast precursors in vivoDeepak H. Balani, Noriaki Ono, and Henry M. Kronenberg http://jci.me/91699

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JCI | Research: Editor’s picks

oncology

Loss of histone methyltransferase SETD2 accelerates Wnt-driven intestinal tumorigenesis

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

Histone methyltransferases are frequently mutated or overexpressed in tumors. Though they represent promising druggable targets for epigenetics-focused cancer therapies, their mechanistic role in tumorigenesis is often unclear. Huairui Yuan, Ni Li, Da Fu, and coworkers investigated the function of the histone methyltransferase SETD2 in colorectal cancer, a disease linked to a gradual accumulation of genetic and epigenetic alterations. In patients with colorectal cancer, reductions in SETD2 expression negatively correlated with disease-free survival. In a mouse model of colorectal cancer, loss of Setd2 accelerated tumor growth by stimulating Wnt-dependent transformation and stemness programs (see the associated image), supporting its role as a tumor suppressor in intestinal cells. Mechanistically, the researchers found that SETD2 deficiency leads to alternative gene splicing, notably in the β-catenin–stabilizing protein DVL2, thereby enhancing Wnt signaling. In the accompanying Commentary, Alberto Kornblihtt highlights this important evidence that epigenetic regulation of gene splicing is a central influence on the pathogenesis of colorectal cancer.

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesisHuairui Yuan, Ni Li, Da Fu, Jiale Ren, Jingyi Hui, Junjie Peng, Yongfeng Liu, Tong Qiu, Min Jiang, Qiang Pan, Ying Han, Xiaoming Wang, Qintong Li, and Jun Qin http://jci.me/94292

Related CommentaryEpigenetics at the base of alternative splicing changes that promote colorectal cancerAlberto R. Kornblihtt http://jci.me/96497

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JCI Review Series

Glia and neurodegenerationSeries Editors: Marco Colonna and David M. Holtzmann

Highlighting the roles of glial cells in neurodegenerative disease

Microglia in steady stateKatrin Kierdorf and Marco Prinz http://jci.me/90602

Understanding the functions and relationships of the glymphatic system and meningeal lymphaticsAntoine Louveau, Benjamin A. Plog, Salli Antila, Kari Alitalo, Maiken Nedergaard, and Jonathan Kipnis http://jci.me/90603

Transcriptional control of microglia phenotypes in health and diseaseInge R. Holtman, Dylan Skola, and Christopher K. Glass http://jci.me/90604

Microglia in prion diseasesAdriano Aguzzi and Caihong Zhu http://jci.me/90605

Microglia in Alzheimer’s diseaseHeela Sarlus and Michael T. Heneka http://jci.me/90606

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementiaDeepti Lall and Robert H. Baloh http://jci.me/90607

Cell biology of spinal cord injury and repairTimothy M. O’Shea, Joshua E. Burda, and Michael V. Sofroniew http://jci.me/90608

CNS inflammation and neurodegenerationTanuja Chitnis and Howard L. Weiner http://jci.me/90609

Oligodendroglia: metabolic supporters of neuronsThomas Philips and Jeffrey D. Rothstein http://jci.me/90610

Glial cells are often considered the supporting actors in the central nervous system. These specialized cells provide structural reinforcement, nutrients, oxygen, and insula-tion to neurons and also clear debris and pathogens from the brain. This Review Series puts the spotlight on glia, highlighting their contributions to brain development, homeostasis, and disease. Emerging evidence points to glia as possible therapeutic targets in the injured or aging brain, and an increased understanding of the mechanisms that underlie their function and dysfunction is driving clini-cal advancements that improve prevention, detection, and treatment of neurodegenerative disease. The reviews in this series unravel the role of glia and the associated glymphatic system in normal physiology, neuronal metabolism, prion diseases, Alzheimer’s disease, ALS, spinal cord injury, and neurodegenerative disease.

Marco Colonna, MD, is the Robert Rock Belliveau Professor of Pathology and Immu-nology at Washington University School of Medicine in St. Louis. His research is broadly focused on mechanisms of innate immunity, including the innate immune mecha-nisms that contribute to Alzheimer’s disease and neurodegeneration. Dr. Colonna’s laboratory discovered the myeloid cell receptor TREM2, and polymorphisms in TREM2 were subsequently identified as risk factors for early-onset dementia and Alzheimer’s disease. His recent work explores the mechanisms by which TREM2 modulates microg-lial function to drive increased susceptibility to Alzheimer’s disease.

David M. Holtzmann, MD, is the Andrew and Gretchen Jones Professor and Chair-man of the Department of Neurology at Washington University School of Medicine in St. Louis. His primary research interest is in the pathogenesis of Alzheimer’s dis-ease and other neurodegenerative disorders. His work has discovered that amyloid-β metabolism is coupled strongly to synaptic activity, a finding with important impli-cations for understanding the heterogenous distribution of amyloid-β deposition throughout the brain. Currently, his laboratory is focusing on identifying biomarkers for Alzheimer’s disease and dementia to improve early detection and treatment.

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Current research articles

angiogenesisYAP/TAZ regulates sprouting angiogenesis and vascular barrier maturationJongshin Kim, Yoo Hyung Kim, Jaeryung Kim, Do Young Park, Hosung Bae, Da-Hye Lee, Kyun Hoo Kim, Seon Pyo Hong, Seung Pil Jang, Yoshiaki Kubota, Young-Guen Kwon, Dae-Sik Lim, and Gou Young Koh http://jci.me/93825

bone biologyParathyroid hormone regulates fates of murine osteoblast precursors in vivo p. 4Deepak H. Balani, Noriaki Ono, and Henry M. Kronenberg http://jci.me/91699

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressivaKyosuke Hino, Kazuhiko Horigome, Megumi Nishio, Shingo Komura, Sanae Nagata, Chengzhu Zhao, Yonghui Jin, Koichi Kawakami, Yasuhiro Yamada, Akira Ohta, Junya Toguchida, and Makoto Ikeya http://jci.me/93521

clinical medicineClinical and immunological responses after CD30-specific chimeric antigen receptor–redirected lymphocytesCarlos A. Ramos, Brandon Ballard, Huimin Zhang, Olga Dakhova, Adrian P. Gee, Zhuyong Mei, Mrinalini Bilgi, Meng-Fen Wu, Hao Liu, Bambi Grilley, Catherine M. Bollard, Bill H. Chang, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Gianpietro Dotti, and Barbara Savoldo http://jci.me/94306

geneticsInborn errors in RNA polymerase III underlie severe varicella zoster virus infectionsBenson Ogunjimi, Shen-Ying Zhang, Katrine B. Sørensen, Kristian A. Skipper, Madalina Carter-Timofte, Gaspard Kerner, Stefanie Luecke, Thaneas Prabakaran, Yujia Cai, Josephina Meester, Esther Bartholomeus, Nikhita Ajit Bolar, Geert Vandeweyer, Charlotte Claes, Yasmine Sillis, Lazaro Lorenzo, Raffaele A. Fiorenza, Soraya Boucherit, Charlotte Dielman, Steven Heynderickx, George Elias, Andrea Kurotova, Ann Vander Auwera, Lieve Verstraete, Lieven Lagae, Helene Verhelst, Anna Jansen, Jose Ramet, Arvid Suls, Evelien Smits, Berten Ceulemans, Lut Van Laer, Genevieve Plat Wilson, Jonas Kreth, Capucine Picard, Horst Von Bernuth, Joël Fluss, Stephane Chabrier, Laurent Abel, Geert Mortier, Sebastien Fribourg, Jacob Giehm Mikkelsen, Jean-Laurent Casanova, Søren R. Paludan, and Trine H. Mogensen http://jci.me/92280

hematologyUltrasensitive mutation detection identifies rare residual cells causing acute myelogenous leukemia relapseBrian Parkin, Angelina Londoño-Joshi, Qing Kang, Muneesh Tewari, Andrew D. Rhim, and Sami N. Malek http://jci.me/91964

immunologyMacrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signalingMiguel Quiros, Hikaru Nishio, Philipp A. Neumann, Dorothee Siuda, Jennifer C. Brazil, Veronica Azcutia, Roland Hilgarth, Monique N. O’Leary, Vicky Garcia-Hernandez, Giovanna Leoni, Mingli Feng, Gabriela Bernal, Holly Williams, Priya H. Dedhia, Christian Gerner-Smidt, Jason Spence, Charles A. Parkos, Timothy L. Denning, and Asma Nusrat http://jci.me/90229

Enlarged pelvic lymph nodes

Inflamed colonic crypts

Retinal blood vessels

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Current research articles

immunologyProlyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses p. 2Pranvera Sadiku, Joseph A. Willson, Rebecca S. Dickinson, Fiona Murphy, Alison J. Harris, Amy Lewis, David Sammut, Ananda S. Mirchandani, Eilise Ryan, Emily R. Watts, A.A. Roger Thompson, Helen M. Marriott, David H. Dockrell, Cormac T. Taylor, Martin Schneider, Patrick H. Maxwell, Edwin R. Chilvers, Massimilliano Mazzone, Veronica Moral, Chris W. Pugh, Peter J. Ratcliffe, Christopher J. Schofield, Bart Ghesquiere,

Peter Carmeliet, Moira K.B. Whyte, and Sarah R. Walmsley http://jci.me/90848

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation p. 1Gregory S. Whitehead, Seddon Y. Thomas, Karim H. Shalaby, Keiko Nakano, Timothy P. Moran, James M. Ward, Gordon P. Flake, Hideki Nakano, and Donald N. Cook http://jci.me/90890

NBEAL2 is required for neutrophil and NK cell function and pathogen defense p. 2John M. Sowerby, David C. Thomas, Simon Clare, Marion Espéli, Jose A. Guerrero, Kim Hoenderdos, Katherine Harcourt, Morgan Marsden, Juneid Abdul-Karim, Mathew Clement, Robin Antrobus, Yagnesh Umrania, Philippa R. Barton, Shaun M. Flint, Jatinder K. Juss, Alison M. Condliffe, Paul A. Lyons, Ian R. Humphreys, Edwin R. Chilvers, Willem H. Ouwehand, Gordon Dougan, and Kenneth G.C. Smith http://jci.me/91684

metabolismStromal cell cadherin-11 regulates adipose tissue inflammation and diabetesSook Kyung Chang, Ayano C. Kohlgruber, Fumitaka Mizoguchi, Xavier Michelet, Benjamin J. Wolf, Kevin Wei, Pui Y. Lee, Lydia Lynch, Danielle Duquette, Victòria Ceperuelo-Mallafré, Alexander S. Banks, and Michael B. Brenner http://jci.me/86881

nephrologyPhenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremiaJames S. Ware, Louise V. Wain, Sarath K. Channavajjhala, Victoria E. Jackson, Elizabeth Edwards, Run Lu, Keith Siew, Wenjing Jia, Nick Shrine, Sue Kinnear, Mahli Jalland, Amanda P. Henry, Jenny Clayton, Kevin M. O’Shaughnessy, Martin D. Tobin, Victor L. Schuster, Stuart Cook, Ian P. Hall, and Mark Glover http://jci.me/89812

neuroscienceThe atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C p. 3Caleb C. Lord, Steven C. Wyler, Rong Wan, Carlos M. Castorena, Newaz Ahmed, Dias Mathew, Syann Lee, Chen Liu, and Joel K. Elmquist http://jci.me/93362

Prolonged human neural stem cell maturation supports recovery in injured rodent CNS p. 3Paul Lu, Steven Ceto, Yaozhi Wang, Lori Graham, Di Wu, Hiromi Kumamaru, Eileen Staufenberg, and Mark H. Tuszynski http://jci.me/92955

Neutrophils in injured lung

Hepatic lipid droplets

Engrafted human neural cells

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Peripherally derived FGF21 promotes remyelination in the central nervous systemMariko Kuroda, Rieko Muramatsu, Noriko Maedera, Yoshihisa Koyama, Machika Hamaguchi, Harutoshi Fujimura, Mari Yoshida, Morichika Konishi, Nobuyuki Itoh, Hideki Mochizuki, and Toshihide Yamashita http://jci.me/94337

Epiregulin and EGFR interactions are involved in pain processing p. 3Loren J. Martin, Shad B. Smith, Arkady Khoutorsky, Claire A. Magnussen, Alexander Samoshkin, Robert E. Sorge, Chulmin Cho, Noosha Yosefpour, Sivaani Sivaselvachandran, Sarasa Tohyama, Tiffany Cole, Thang M. Khuong, Ellen Mir, Dustin G. Gibson, Jeffrey S. Wieskopf, Susana G. Sotocinal, Jean Sebastien Austin, Carolina B. Meloto, Joseph H. Gitt, Christos Gkogkas, Nahum Sonenberg, Joel D. Greenspan, Roger B. Fillingim, Richard Ohrbach, Gary D. Slade, Charles Knott, Ronald Dubner, Andrea G. Nackley, Alfredo Ribeiro-da-Silva, G. Gregory Neely, William Maixner, Dmitri V. Zaykin, Jeffrey S. Mogil, and Luda Diatchenko http://jci.me/87406

oncologyTreg depletion potentiates checkpoint inhibition in claudin-low breast cancer p. 4Nicholas A. Taylor, Sarah C. Vick, Michael D. Iglesia, W. June Brickey, Bentley R. Midkiff, Karen P. McKinnon, Shannon Reisdorf, Carey K. Anders, Lisa A. Carey, Joel S. Parker, Charles M. Perou, Benjamin G. Vincent, and Jonathan S. Serody http://jci.me/90499

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis p. 5Huairui Yuan, Ni Li, Da Fu, Jiale Ren, Jingyi Hui, Junjie Peng, Yongfeng Liu, Tong Qiu, Min Jiang, Qiang Pan, Ying Han, Xiaoming Wang, Qintong Li, and Jun Qin http://jci.me/94292

GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition p. 4

Francis O. Enane, Wai Ho Shuen, Xiaorong Gu, Ebrahem Quteba, Bartlomiej Przychodzen, Hideki Makishima, Juraj Bodo, Joanna Ng, Chit Lai Chee, Rebecca Ba, Lip Seng Koh, Janice Lim, Rachael Cheong, Marissa Teo, Zhenbo Hu, Kwok Peng Ng, Jaroslaw Maciejewski, Tomas Radivoyevitch, Alexander Chung, London Lucien Ooi, Yu Meng Tan, Peng-Chung Cheow, Pierce Chow, Chung Yip Chan, Kiat Hon Lim, Lisa Yerian, Eric Hsi, Han Chong Toh, and Yogen Saunthararajah http://jci.me/93488

The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancerWanjin Li, Zihan Zhang, Xinhua Liu, Xiao Cheng, Yi Zhang, Xiao Han, Yu Zhang, Shumeng Liu, Jianguo Yang, Bosen Xu, Lin He, Luyang Sun, Jing Liang, and Yongfeng Shang http://jci.me/94233

stem cells27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancyHideyuki Oguro, Jeffrey G. McDonald, Zhiyu Zhao, Michihisa Umetani, Philip W. Shaul, and Sean J. Morrison http://jci.me/94027

Intestinal tumor enterocytes

Hematopoietic progenitors in spleen

Myelination in spinal cord

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Editor’s picks

Interrogating the effects of rapamycin on pulmonary lymphatic malformation

vascular biology

The lymphatic malformation pulmonary lymphangiectasia is characterized by an expansion of lymphatic vessels in the lung. Inhibition of mTOR signaling with rapamycin has shown some benefit for patients with lymphatic malformation; however, the mechanisms by which rapamycin mediates improvement are poorly defined. Peter Baluk and colleagues used a murine model of pulmonary lymphangiectasia to evaluate rapamycin in the prevention and/or reversal of lymphatic abnormali-ties. Rapamycin prevented lymphatic endothelial cell proliferation and limited the development of lymphatic abnormalities (see the accompanying image) and promoted a partial regression of established lymphangiectasia without effecting normal lymphatics. Together, the results of this study provide insight into the clinical benefit observed with rapamycin treatment and support further evaluation of this particular model of lymphatic malformation.

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tractPeter Baluk, Li-Chin Yao, Julio C. Flores, Dongwon Choi, Young-Kwon Hong, and Donald M. McDonald http://jci.me/90103

Sex-specific metabolic differences linked to glioma outcome

oncology

While sex is now recognized as an important factor in the clinical manifestation and outcome of many diseases, including several forms of cancer, the drivers of sex-dependent differences are not fully understood. Joseph Ippolito and colleagues performed a retrospective analysis of transcriptomic data in The Cancer Genome Atlas collected from patients with low-grade gliomas and determined that male-specific overexpression of glycolytic genes associates with decreased survival. Conversely, increased expression of glycolytic genes and the presence of IDH mutation in females was linked to longer survival. Furthermore, evaluation of metabolite data

from an independent cohort of grade 2 gliomas confirmed that overall survival was decreased in males with altered levels of glycolytic metabolites. This apparent synergy between sex and tumor metabolism has potential to be exploited to better define glioma patient prognosis.

Sexual dimorphism in glioma glycolysis underlies sex differences in survivalJoseph E. Ippolito, Aldrin Kay-Yuen Yim, Jingqin Luo, Prakash Chinnaiyan, and Joshua B. Rubin http://jci.me/92142

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JCI Insight | Editor’s picks

clinical medicine

immunlogy

Atypical T cell population develops in response to early pathogen exposureThe adaptive immune response is the culmination of an individual’s exposure to different pathogens and antigens throughout life. Chronic infection is associated with T cell exhaustion; however, the effect of early pathogen exposure is not well understood. Ann Moormann and colleagues analyzed CD4+ and CD8+ T cell popula-tions in children from areas with different burdens of malaria, schistosomiasis, and EBV. Samples were collected from children as toddlers and then again when they were school-aged. As toddlers, there was no notable difference in T cell populations based on pathogen burden; however, at the later collection, children living in a high-pathogen-exposure area developed an atypical population of CD8dim T cells with an innate-like profile, stunted proliferation, and impaired T cell receptor signaling. The CD8dim T cells identified in this study appear to represent a distinct population that should be further characterized.

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cellsYves T. Falanga, Michela Frascoli, Yasin Kaymaz, Catherine Forconi, John Michael Ong’echa, Jeffrey A. Bailey, Leslie J. Berg, and Ann M. Moormann http://jci.me/93814

Noninvasive imaging of retinal amyloid deposits in patients with Alzheimer’s diseaseEarly and definitive diagnosis of Alzheimer’s disease (AD) is a major challenge that limits the application of disease-modifying therapies before substantive neurodegeneration. Recent studies from the Koronyo-Hamaoui lab and others have identified amyloid β-protein (Aβ) deposits in the retinas of patients with AD and rodent models. Moreover, noninvasive imaging techniques using curcumin, which has a high affinity for Aβ, have been shown to accurately detect and monitor amyloid deposition in the retina of rodent AD models. In this study, Yosef Koronyo and colleagues translated this imaging approach to characterize the pathological hallmark of AD, Aβ deposition, in the retinas of patients with AD and healthy controls. Consistent with histological and ultrastruc-tural observations, live retinal imaging enabled the detection and quantification of these plaques and revealed an increased burden of curcumin-positive deposits in patients with AD compared with controls (see the accompanying image), supporting further development of this approach as a tool for screening those at risk of AD.

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s diseaseYosef Koronyo, David Biggs, Ernesto Barron, David S. Boyer, Joel A. Pearlman, William J. Au, Shawn J. Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M. Cole, Carol A. Miller, David R. Hinton, Steven R. Verdooner, Keith L. Black, and Maya Koronyo-Hamaoui http://jci.me/93621

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JCI Insight | Editor’s picks

Targeting CCR6 in inflammatory disease

autoimmunity

The chemokine receptor CCR6 is expressed on the surface of pathogenic immune cells, including those that secrete IL-17 and IL-22, and mediates the recruitment of these cells to sites of inflammation. CCR6-expressing cells have been implicated in a variety of inflammatory and autoimmune diseases; therefore, targeting this receptor has therapeutic potential. Remy Robert and colleagues developed transgenic mice that express human CCR6 (hCCR6) in the native Ccr6 locus and a humanized, antagonistic antibody against hCCR6. Treatment of hCCR6-expressing mice with anti-hCCR6 markedly improved inflammation and disease-associated phenotypes in animals with imiquimod-induced psoriasis (see the accompanying image) and experimental autoimmune encephalitis (EAE), supporting further exploration of targeting CCR6 for treatment of Th17-mediated diseases.

Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin miceRemy Robert, Caroline Ang, Guizhi Sun, Laurent Juglair, Ee X. Lim, Linda J. Mason, Natalie L. Payne, Claude C.A. Bernard, and Charles R. Mackay http://jci.me/94821

Irgm1 is a key player in mucosal immunityThe autoimmune disease Sjogren’s syndrome (SS) is characterized by the accumulation of immune cells at mucosal sites, such as the eyes, mouth, intestine, and lung. The disease pathogenesis is not fully understood, and mouse models of SS are limited. Kathleen Azzam and colleagues determined that mice lacking the IFN-inducible cytoplasmic GTPase Irgm1 exhibit SS-associated phenotypes, including lymphocytic infiltration at multiple mucosal sites and development of IgA class autoantibodies. In the lung, Igrm1 deficiency increased production of T15, an idiotype IgA that recognizes both host and pneumococcal phosphoryl-choline. Accordingly, Streptococcus pneumoniae opsonization and clearance were enhanced in Igrm1–/– mice, resulting in increased survival.

Together, the results of this study indicate that Igrm1 plays a critical role in the regulation of mucosal immunity and host defense and provide an animal model of primary SS.

Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfacesKathleen M. Azzam, Jennifer H. Madenspacher, Derek W. Cain, Lihua Lai, Kymberly M. Gowdy, Prashant Rai, Kyathanahalli Janardhan, Natasha Clayton, Willie Cunningham, Heather Jensen, Preeyam S. Patel, John F. Kearney, Gregory A. Taylor, and Michael B. Fessler http://jci.me/91914

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Current articles

Mapping the clinical outcomes and genetic evolution of Ebola virus in Sierra LeoneTao Li, Hong-Wu Yao, Di Liu, Hong-Guang Ren, Yi Hu, David Kargbo, Yue Teng, Yong-Qiang Deng, Hui-Jun Lu, Xiong Liu, Kun Liu, Li-Qun Fang, Nian-Zhi Ning, Gary Wong, Foday Dafae, Abdul Kamara, AiPing Wu, Tai-Jiao Jiang, Zhan Li, Jie Huang, Yu Sun, Jun Qian, Brima Kargbo, Jia-Fu Jiang, Hui Wang, and Wu-Chun Cao http://jci.me/88333

Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in miceToshihiro Inubushi, Satoshi Nozawa, Kazu Matsumoto, Fumitoshi Irie, and Yu Yamaguchi http://jci.me/90049

Sexual dimorphism in glioma glycolysis underlies sex differences in survival p. 10Joseph E. Ippolito, Aldrin Kay-Yuen Yim, Jingqin Luo, Prakash Chinnaiyan, and Joshua B. Rubin http://jci.me/92142

Plasminogen promotes cholesterol efflux by the ABCA1 pathwayNathalie Pamir, Patrick M. Hutchins, Graziella E. Ronsein, Hao Wei, Chongren Tang, Riku Das, Tomas Vaisar, Edward Plow, Volker Schuster, Catherine A. Reardon, Richard Weinberg, David A. Dichek, Santica Marcovina, Godfrey S. Getz, and Jay W. Heinecke http://jci.me/92176

Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan miceRosanne Rouf, Elena Gallo MacFarlane, Eiki Takimoto, Rahul Chaudhary, Varun Nagpal, Peter P. Rainer, Julia G. Bindman, Elizabeth E. Gerber, Djahida Bedja, Christopher Schiefer, Karen L. Miller, Guangshuo Zhu, Loretha Myers, Nuria Amat-Alarcon, Dong I. Lee, Norimichi Koitabashi, Daniel P. Judge, David A. Kass, and Harry C. Dietz http://jci.me/91588

Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesisYu Fukuda, Yao Wang, Shangli Lian, John Lynch, Shinjiro Nagai, Bruce Fanshawe, Ayten Kandilci, Laura J. Janke, Geoffrey Neale, Yiping Fan, Brian P. Sorrentino, Martine F. Roussel, Gerard Grosveld, and John D. Schuetz http://jci.me/92409

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failureDuane D. Hall, Jessica M. Ponce, Biyi Chen, Kathryn M. Spitler, Adrianne Alexia, Gavin Y. Oudit, Long-Sheng Song, and Chad E. Grueter http://jci.me/92476

Integration of homeostatic signaling and food reward processing in the human brainJoe J. Simon, Anne Wetzel, Maria Hamze Sinno, Mandy Skunde, Martin Bendszus, Hubert Preissl, Paul Enck, Wolfgang Herzog, and Hans-Christoph Friederich http://jci.me/92970

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanismsDelphine Planas, Yuwei Zhang, Patricia Monteiro, Jean-Philippe Goulet, Annie Gosselin, Nathalie Grandvaux, Thomas J. Hope, Ariberto Fassati, Jean-Pierre Routy, and Petronela Ancuta http://jci.me/93230

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancerSharon Wang, Jeff C. Liu, YoungJun Ju, Giovanna Pellecchia, Veronique Voisin, Dong-Yu Wang, Rajwinder Lehal, Yaacov Ben-David, Gary D. Bader, and Eldad Zacksenhaus http://jci.me/93313

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophyTsukasa Shimauchi, Takuro Numaga-Tomita, Tomoya Ito, Akiyuki Nishimura, Ryosuke Matsukane, Sayaka Oda,

Sumio Hoka, Tomomi Ide, Norimichi Koitabashi, Koji Uchida, Hideki Sumimoto, Yasuo Mori, and Motohiro Nishida http://jci.me/93358

Perichondrial cells

Enlarged cardiomyocytes

Mammary gland tissue

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Current articles

Dichotomous miR expression and immune responses following primary blood-stage malariaJulie G. Burel, Simon H. Apte, Penny L. Groves, Michelle J. Boyle, Christine Langer, James G. Beeson, James S. McCarthy, and Denise L. Doolan http://jci.me/93434

A CCR2+ myeloid cell niche required for pancreatic β cell growthKristin Mussar, Stephanie Pardike, Tobias M. Hohl, Gary Hardiman, Vincenzo Cirulli, and Laura Crisa http://jci.me/93834

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells p. 11Yves T. Falanga, Michela Frascoli, Yasin Kaymaz, Catherine Forconi, John Michael Ong’echa,

Jeffrey A. Bailey, Leslie J. Berg, and Ann M. Moormann http://jci.me/93814

Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative Dixon MRIYue Zhang, Durga Udayakumar, Ling Cai, Zeping Hu, Payal Kapur, Eun-Young Kho, Andrea Pavía-Jiménez, Michael Fulkerson, Alberto Diaz de Leon, Qing Yuan, Ivan E. Dimitrov, Takeshi Yokoo, Jin Ye, Matthew A. Mitsche, Hyeonwoo Kim, Jeffrey G. McDonald, Yin Xi, Ananth J. Madhuranthakam, Durgesh K. Dwivedi, Robert E. Lenkinski, Jeffrey A. Cadeddu, Vitaly Margulis, James Brugarolas, Ralph J. DeBerardinis, and Ivan Pedrosa http://jci.me/94278

Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitisKyoko Tomita, Rohit Kohli, Brittany L. MacLaurin, Petra Hirsova, Qianqian Guo, Luz H. Gutierrez Sanchez, Harris A. Gelbard, Burns C. Blaxall, and Samar H. Ibrahim http://jci.me/94488

Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice p. 12

Remy Robert, Caroline Ang, Guizhi Sun, Laurent Juglair, Ee X. Lim, Linda J. Mason, Natalie L. Payne, Claude C.A. Bernard, and Charles R. Mackay http://jci.me/94821

Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammationDenise Tischner, Myriam Grimm, Harmandeep Kaur, Daniel Staudenraus, Jorge Carvalho, Mario Looso, Stefan Günther, Florian Wanke, Sonja Moos, Nelly Siller, Johanna Breuer, Nicholas Schwab, Frauke Zipp, Ari Waisman, Florian C. Kurschus, Stefan Offermanns, and Nina Wettschureck http://jci.me/95063

MTG16 is a tumor suppressor in colitis-associated carcinomaElizabeth M. McDonough, Caitlyn W. Barrett, Bobak Parang, Mukul K. Mittal, J. Joshua Smith, Amber M. Bradley, Yash A. Choksi, Lori A. Coburn, Sarah P. Short, Joshua J. Thompson, Baolin Zhang, Shenika V. Poindexter, Melissa A. Fischer, Xi Chen, Jiang Li, Frank L. Revetta, Rishi Naik, M. Kay Washington, Michael J. Rosen, Scott W. Hiebert, Keith T. Wilson, and Christopher S. Williams http://jci.me/78210

Parasympathetic dysfunction and antiarrhythmic effect of vagal nerve stimulation following myocardial infarctionMarmar Vaseghi, Siamak Salavatian, Pradeep S. Rajendran, Daigo Yagishita, William R. Woodward, David Hamon, Kentaro Yamakawa, Tadanobu Irie, Beth A. Habecker, and Kalyanam Shivkumar http://jci.me/86715

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract p. 10Peter Baluk, Li-Chin Yao, Julio C. Flores, Dongwon Choi, Young-Kwon Hong, and Donald M. McDonald http://jci.me/90103

Pancreatic myeloid and β cells

Collagen deposits in liver

Colonic epithelium

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Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces p. 12Kathleen M. Azzam, Jennifer H. Madenspacher, Derek W. Cain, Lihua Lai, Kymberly M. Gowdy, Prashant Rai, Kyathanahalli Janardhan, Natasha Clayton, Willie Cunningham, Heather Jensen, Preeyam S. Patel, John F. Kearney, Gregory A. Taylor, and Michael B. Fessler http://jci.me/91914

Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosisLynne A. Murray, David M. Habiel, Miriam Hohmann, Ana Camelo, Huilan Zhang, Yang Zhou, Ana Lucia Coelho, Xueyan Peng, Mridu Gulati, Bruno Crestani, Matthew A. Sleeman, Tomas Mustelin, Meagan Moore, Changwan Ryu, Awo D. Osafo-Addo, Jack A. Elias, Chun G. Lee, Buqu Hu, Jose D. Herazo-Maya, Darryl A. Knight, Cory M. Hogaboam, and Erica L. Herzog http://jci.me/92192

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent mannerSoohyun P. Kim, Zhu Li, Meredith L. Zoch, Julie L. Frey, Caitlyn E. Bowman, Priyanka Kushwaha, Kathleen A. Ryan, Brian C. Goh, Susanna Scafidi, Julie E. Pickett, Marie-Claude Faugere, Erin E. Kershaw, Daniel L. J. Thorek, Thomas L. Clemens, Michael J. Wolfgang, and Ryan C. Riddle http://jci.me/92704

HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversalGuoxin Wu, Michael Swanson, Aarthi Talla, Donald Graham, Julie Strizki, Daniel Gorman, Richard J.O. Barnard, Wade Blair, Ole S. Søgaard, Martin Tolstrup, Lars Østergaard, Thomas A. Rasmussen, Rafick-Pierre Sekaly, Nancie M. Archin, David M. Margolis, Daria J. Hazuda, and Bonnie J. Howell http://jci.me/92901

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagensArchana S. Nagaraja, Robert L. Dood, Guillermo Armaiz-Pena, Yu Kang, Sherry Y. Wu, Julie K. Allen, Nicholas B. Jennings, Lingegowda S. Mangala, Sunila Pradeep, Yasmin Lyons, Monika Haemmerle, Kshipra M. Gharpure, Nouara C. Sadaoui, Cristian Rodriguez-Aguayo, Cristina Ivan, Ying Wang, Keith Baggerly, Prahlad Ram, Gabriel Lopez-Berestein, Jinsong Liu, Samuel C. Mok, Lorenzo Cohen, Susan K. Lutgendorf, Steve W. Cole, and Anil K. Sood http://jci.me/93076

VIPAR, a quantitative approach to 3D histopathology applied to lymphatic malformationsRené Hägerling, Dominik Drees, Aaron Scherzinger, Cathrin Dierkes, Silvia Martin-Almedina, Stefan Butz, Kristiana Gordon, Michael Schäfers, Klaus Hinrichs, Pia Ostergaard, Dietmar Vestweber, Tobias Goerge, Sahar Mansour, Xiaoyi Jiang, Peter S. Mortimer, and Friedemann Kiefer http://jci.me/93424

Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2Marcin L. Pekalski, Arcadio Rubio García, Ricardo C. Ferreira, Daniel B. Rainbow, Deborah J. Smyth, Meghavi Mashar, Jane Brady, Natalia Savinykh, Xaquin Castro Dopico, Sumiyya Mahmood, Simon Duley, Helen E. Stevens, Neil M. Walker, Antony J. Cutler, Frank Waldron-Lynch, David B. Dunger, Claire Shannon-Lowe, Alasdair J. Coles, Joanne L. Jones, Chris Wallace, John A. Todd, and Linda S. Wicker http://jci.me/93739

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease p. 11Yosef Koronyo, David Biggs, Ernesto Barron, David S. Boyer, Joel A. Pearlman, William J. Au, Shawn J. Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M. Cole, Carol A. Miller, David R. Hinton, Steven R. Verdooner, Keith L. Black, and Maya Koronyo-Hamaoui http://jci.me/93621

Human lung tumor FOXP+ Tregs upregulate four “Treg-locking” transcription factorsTatiana Akimova, Tianyi Zhang, Dmitri Negorev, Sunil Singhal, Jason Stadanlick, Abhishek Rao, Michael Annunziata, Matthew H. Levine, Ulf H. Beier, Joshua M. Diamond, Jason D. Christie, Steven M. Albelda, Evgeniy B. Eruslanov, and Wayne W. Hancock http://jci.me/94075

Lung parenchymal lesion

Cross section of human retina

Collagen expression in a tumor

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JCI Insight | Current articles

Injury-induced actin cytoskeleton reorganization in podocytes revealed by super-resolution microscopyHani Y. Suleiman, Robyn Roth, Sanjay Jain, John E. Heuser, Andrey S. Shaw, and Jeffrey H. Miner http://jci.me/94137

Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease

Zoheb B. Kazi, Ankit K. Desai, Kathryn L. Berrier, R. Bradley Troxler, Raymond Y. Wang, Omar A. Abdul-Rahman, Pranoot Tanpaiboon, Nancy J. Mendelsohn, Eli Herskovitz, David Kronn, Michal Inbar-Feigenberg, Catherine Ward-Melver, Michelle Polan, Punita Gupta, Amy S. Rosenberg, and Priya S. Kishnani http://jci.me/94328

Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonistMegha Garg, Adriana A. de Jesus, Dawn Chapelle, Paul Dancey, Ronit Herzog, Rafael Rivas-Chacon, Theresa L. Wampler Muskardin, Ann Reed, James C. Reynolds, Raphaela Goldbach-Mansky, and Gina A. Montealegre Sanchez http://jci.me/94838

Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlled trialSamar Farha, Didem Saygin, Margaret M. Park, Hoi I. Cheong, Kewal Asosingh, Suzy A.A. Comhair, Olivia R. Stephens, Emir C. Roach, Jacqueline Sharp, Kristin B. Highland, Frank P. DiFilippo, Donald R. Neumann, W.H. Wilson Tang, and Serpil C. Erzurum http://jci.me/95240

Podocyte foot processes

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

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

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

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