jci.org/this-month

Immune drivers of tuberculosis reactivation 3

Stromal galectin-1 limits lymphocyte migration to tumors 3

Dermal white adipose tissue supports skin homeostasis 4

Stress-induced MDSC activation suppresses antitumor immunity 5

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

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December 2019

This Month

Preventing hemoglobin-induced damage in cerebral arteries p. 2

Journal of Clinical Investigation Consulting Editors

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j c i . o r g / t h i s - m o n t h d e c e m b e r 2 0 1 9 1

For the JCIEditorRexford S. Ahima

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

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

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

BiostatisticianEliseo Guallar

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Staff EditorsExecutive EditorSarah C. Jackson

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JCI This Month ISSN 2324-7703 (print);ISSN 2325-4556 (online)

For the full JCI online: jci.me/129/12

This MonthDecember 2019

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

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

(ASCI) indicates corresponding authors who are ASCI members.

The 2019 Nobel Prize in Physiology or Medicine was awarded to Gregg L. Semenza (Johns Hopkins University, JCI Deputy Editor and ASCI member), William G. Kaelin Jr. (Dana-Farber Cancer Institute and ASCI member), and Sir Peter J. Ratcliffe (University of Oxford) for their discoveries of the mechanisms underlying cellular sensing of oxygen levels and regulation of physiologic hypoxia. Each of these physician-scientists was intrigued by a different clinically relevant observation and utilized basic biochemical tools to address their questions. What is remarkable is how the three separate lines of investigation converged, delineating a central cellular pathway that has far-reaching implications for our understanding of human physiology, disease states, and medicine.

In the accompanying Viewpoint, Javid Moslehi and W. Kimryn Rathmell describe the enormous contribution of this year’s Nobel Prize winners to establishing the field of hypoxia. Semenza discovered a hypoxia-responsive DNA-binding site in the erythropoietin gene and the nuclear factor, which he termed hypoxia-inducible factor 1 (HIF-1), that drives its transcription. He found that in addition to erythropoietin, HIF induces a number of other genes required for systemic response to hypoxia, including VEGF. Simultaneously, Kaelin was studying von Hippel–Lindau disease, a rare genetic syndrome in which mutations in the affected gene (VHL) lead to cancers such as renal cell carcinoma and cerebellar hemangioblastomas. Kaelin’s group showed that VHL is a component of a ubiquitin ligase complex that is critical for regulation of hypoxia-inducible genes. The crucial observation connecting these lines of research came from the Ratcliffe group, which demonstrated that VHL regulates HIF-1. The Kaelin and Ratcliffe groups subsequently demonstrated that HIF-1 is transcribed, translated, and quickly degraded by the VHL complex, unless oxygen becomes limiting.

The discovery of the HIF pathway revealed that all cells are capable of sensing and responding to oxygen levels. In turn, hypoxia response is fundamental for development and physiological homeostasis, and is dysregulated in a wide range of diseases, including cancer, cardiovascular disease, pulmonary hypertension, and stroke. Through fundamental research, Semenza, Kaelin, and Ratcliffe unraveled how cells respond to hypoxia and launched a field with broad implications for physiology and medicine.

ViewpointThe 2019 Nobel Prize honors fundamental discoveries in hypoxia responseJavid Moslehi and W. Kimryn Rathmell http://jci.org/134813

Congratulations to Nobel Prize winners Semenza, Kaelin, and Ratcliffe

j c i . o r g / t h i s - m o n t h d e c e m b e r 2 0 1 92

research

Editor’s picks

on the jci cover vascular biology

Haptoglobin blocks hemoglobin-induced vasospasm in cerebral arteries

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasmMichael Hugelshofer, Raphael M. Buzzi, Christian A. Schaer, Henning Richter, Kevin Akeret, Vania Anagnostakou, Leila Mahmoudi, Raphael Vaccani, Florence Vallelian, Jeremy W. Deuel, Peter W. Kronen, Zsolt Kulcsar, Luca Regli, Jin Hyen Baek, Ivan S. Pires, Andre F. Palmer, Matthias Dennler, Rok Humar, Paul W. Buehler, Patrick R. Kircher, Emanuela Keller, and Dominik J. Schaer http://jci.me/130630

Myeloid beclin 1 controls neutrophil-mediated inflammation and B cell tumorigenesis in mice

oncology

Neutrophils adopt either protumor or antitumor functions that substantially influence the tumor’s immune environment. In addition to stimulating cytokine release and phagocytosis and releasing neutrophil extracellular traps, some neutrophils influence B cell activation and have been linked to lymphoid tumor development. Peng Tan and colleagues explored the role of the autophagy-related protein beclin 1 in lymphoid cancer development after observing that myeloid-specific beclin 1 loss triggered neutrophil-driven B cell malignancies in mice. They discovered that aberrant p38 activation in beclin 1–deficient neutrophils enhanced neutrophil–B cell interactions, leading to increased expression of the immunosuppressive ligand PD-L1 in B cells. In human pre-B cell malignancy, low beclin 1 levels correlated with increased PD-L1 expression. Yu-Lin Su and Marcin

Kortylewski discuss clinical implications of the finding that myeloid beclin 1 contributes to antitumor immunity in the accompanying Commentary.

Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma developmentPeng Tan, Lian He, Changsheng Xing, Jingrong Mao, Xiao Yu, Motao Zhu, Lixia Diao, Leng Han, Yubin Zhou, James M. You, Helen Y. Wang, and Rong-Fu Wang http://jci.me/127721

Related CommentaryBeclin 1 as a neutrophil-specific immune checkpointYu-Lin Su and Marcin Kortylewski http://jci.me/132534

Aneurysms and head injuries can cause bleeding into the subarachnoid space, a layer of cerebrospinal fluid (CSF) surrounding the brain. As erythrocytes are cleared from CSF, they release hemoglobin, producing neurotoxic effects that are associated with serious complications during recovery, including delayed ischemic neurological deficit (DIND). In this issue of the JCI, Michael Hugelshofer, Raphael Buzzi, and colleagues examined CSF samples from patients diagnosed with DIND after subarachnoid hemorrhage. In an ex vivo model, they confirmed that hemoglobin accumulation in the patients’ CSF impaired nitric oxide–mediated vasodilation. They next used haptoglobin, an endogenous hemoglobin scavenger, to sequester cell-free hemoglobin present in CSF. When infused into sheep subarachnoid space, haptoglobin-mediated scavenging of hemoglobin normalized nitric oxide signaling and mitigated pathological vasoconstriction. These findings support further investigation of haptoglobin as a strategy to prevent or reduce DIND and other hemoglobin-driven complications of subarachnoid hemorrhage. The cover image is a drawing depicting hemoglobin (red) in the tiny CSF space alongside small penetrating cerebral arteries (green) of the sheep brain. Whereas free hemoglobin penetrates from CSF into the vascular smooth muscle layer (lower artery) and into the brain tissue, haptoglobin blocks hemoglobin translocation and its vasoconstrictive effect (upper artery). Image credit: Rok Humar.

j c i . o r g / t h i s - m o n t h d e c e m b e r 2 0 1 9 3

JCI | Research: Editor’s picks

Rethinking tuberculosis reactivation mechanisms in HIV-infected individuals

aids/hiv

Most healthy individuals successfully contain Mycobacterium tuberculosis (Mtb) infection, but latent tuberculosis infections can reactivate if the immune system is compromised. Individuals with HIV are at major risk for tuberculosis reactivation, which is thought to result from depletion of Mtb-controlling CD4+ T cells. Allison Bucşan and colleagues’ observations in models of Mtb and SIV coinfection in nonhuman primates challenge this assumption. CD4+ T cell depletion alone did not reactivate latent tuberculosis infection. Rather, SIV-driven tuberculosis reactivation was associated with chronic immune activation and its effects on T cell phenotypes and homeostatic dysfunction. Bucşan et al.’s findings support a more complex model for tuberculosis reactivation in HIV-infected individuals that may provide important insights for new therapeutics. The accompanying images compare CD4+ T cells (red) during antibody-mediated CD4+ T cell depletion (top) and during SIV-mediated tuberculosis reactivation (bottom) in Mtb-infected nonhuman primate lung tissue.

Mechanisms of reactivation of latent tuberculosis infection due to SIV coinfectionAllison N. Bucşan, Ayan Chatterjee, Dhiraj K. Singh, Taylor W. Foreman, Tae-Hyung Lee, Breanna Threeton, Melanie G. Kirkpatrick, Mushtaq Ahmed, Nadia Golden, Xavier Alvarez, James A. Hoxie, Smriti Mehra, Jyothi Rengarajan, Shabaana A. Khader, and Deepak Kaushal http://jci.me/125810

oncology

Tumor-derived galectin-1 promotes an immunosuppressive barrier at the tumor endotheliumAn immunosuppressive tumor microenvironment is a hallmark of cancer progression as well as a barrier to the efficacy of immunotherapeutic strategies, which rely on effector T cell infiltration into the tumor site. Dhanya Nambiar and colleagues sought to identify mechanisms underlying immunosuppression in head and neck cancer (HNC), in which galectin-1 expression has been linked to advanced disease and low T cell infiltration. T cell migration substantially decreased when endothelial cells were preconditioned with physiological concentrations of galectin-1. Mechanistically, they determined that tumor-secreted galectin-1 enhanced PD-L1 expression in the tumor endothelium, thereby impairing T cell migration to tumors. In syngeneic mouse models of HNC, blocking galectin-1 improved the response to anti-PD1 immunotherapy alone or in combination with radiotherapy, supporting the role of galectin-1 in creating an immunosuppressive barrier in this disease. In the accompany-

ing Commentary, Asmi Chakraborty and Charles Dimitroff discuss tumor glycobiology as a potential strategy for improving treatment outcome.

Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistanceDhanya K. Nambiar, Todd Aguilera, Hongbin Cao, Shirley Kwok, Christina Kong, Joshua Bloomstein, Zemin Wang, Vangipuram S. Rangan, Dadi Jiang, Rie von Eyben, Rachel Liang, Sonya Agarwal, A. Dimitrios Colevas, Alan Korman, Clint T. Allen, Ravindra Uppaluri, Albert C. Koong, Amato Giaccia, and Quynh Thu Le http://jci.me/129025

Related CommentaryCancer immunotherapy needs to learn how to stick to its gunsAsmi Chakraborty and Charles J. Dimitroff http://jci.me/133415

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JCI | Research: Editor’s picks

SLC30A10-mediated manganese excretion is critical for balancing manganese levels

High plasticity and reversible dedifferentiation distinguish dermal adipose tissue

metabolism

Manganese is an essential cofactor in multiple immune and endocrine processes, in hematopoiesis, and in oxidative stress responses. Multiple manganese transporters in the liver and intestine coordinate manganese absorption and excretion to prevent toxic overload. Courtney Mercadante and colleagues focused on the manganese transporter SLC30A10, which is mutated in patients with manganese excess, cirrhosis, dystonia, and polycythemia. Using a mouse model of the disease that recapitulates key patient phenotypes, the authors reveal that SLC30A10-mediated manganese excretion is essential for preventing manganese excess. Together, the findings provide important insights into the critical function of SLC30A10 in manganese homeostasis. In the accompanying Commen-tary, Nathan Katz and Daniel Rader describe potential therapeutic avenues highlighted by the observations of Mercadante et al.

Manganese transporter Slc30a10 controls physiological manganese excretion and toxicityCourtney J. Mercadante, Milankumar Prajapati, Heather L. Conboy, Miriam E. Dash, Carolina Herrera, Michael A. Pettiglio, Layra Cintron-Rivera, Madeleine A. Salesky, Deepa B. Rao, and Thomas B. Bartnikas http://jci.me/129710

Related CommentaryManganese homeostasis: from rare single-gene disorders to complex phenotypes and diseasesNathan Katz and Daniel J. Rader (ASCI) http://jci.me/133120

White adipose tissue (WAT) serves as the primary site of energy storage in mammals. Location-specific WAT depots display different characteristics and functional roles. Zhuzhen Zhang, Mengle Shao, and colleagues explored the depot-specific characteristics of murine dermal WAT (dWAT), a skin-associated WAT. The team identified Camp as a marker gene for dWAT and determined the transcription profile of dWAT

during hair cycling. Their findings also highlight a role of mature dermal adipocytes in hair cycling and wound healing. Notably, the team observed that murine dWAT expands in both cell size and cell number in extremely obese mice and upon topical application of rosiglitazone, a PPARγ agonist (see the accompanying image). Combined pulse-chase lineage tracing and single-cell RNA sequencing revealed that dWAT has a high level of

plasticity, undergoing dedifferentiation and redifferentiation in response to physiologic (e.g., hair cycling) and pathophysiologic challenges. Together, the findings underscore dWAT’s essential functional role in maintaining skin homeostasis in response to changing physiological conditions.

Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in miceZhuzhen Zhang, Mengle Shao, Chelsea Hepler, Zhenzhen Zi, Shangang Zhao, Yu A. An, Yi Zhu, Alexandra Ghaben, May-yun Wang, Na Li, Toshiharu Onodera, Nolwenn Joffin, Clair Crewe, Qingzhang Zhu, Lavanya Vishvanath, Ashwani Kumar, Chao Xing, Qiong A. Wang, Laurent Gautron, Yingfeng Deng, Ruth Gordillo, Ilja Kruglikov, Christine M. Kusminski, Rana K. Gupta, and Philipp E. Scherer http://jci.me/130239

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JCI | Research: Editor’s picks

CAR-induced BCL11B suppression produces a killer cellular therapyChimeric antigen receptors (CARs) engineered into T cells represent a potentially curative approach to multiple high-risk leukemias. However, current CAR therapies use autologous T cells that are personalized to individual patient antigens, leading to variable quality and quantity, high cost, and treatment delays. Marcel Maluski and colleagues developed CAR-engineered hematopoietic progenitor cells as a strategy for generating lymphoid precursors that are tolerated in a wide range of recipients. By targeting the essential lymphoid transcription factor BCL11B, the CAR-engineered cells blocked T cell development and promoted development of an NK cell–like population when adoptively transferred into mice. These NK-like cells, termed CAR-induced killer (CARiK) cells, demonstrated potent antileukemic activity in both MHC-matched and -mismatched recipients. In the accompanying Commentary, Brigett Brandjes and Marco Davila describe the potential for using CARiK cells to produce an “off-the-shelf” cellular therapy that could avoid some limitations of individualized CAR-based therapies.

Chimeric antigen receptor–induced BCL11B suppression propagates NK-like cell developmentMarcel Maluski, Arnab Ghosh, Jessica Herbst, Vanessa Scholl, Rolf Baumann, Jochen Huehn, Robert Geffers, Johann Meyer, Holger Maul, Britta Eiz-Vesper, Andreas Krueger, Axel Schambach, Marcel R. M. van den Brink, and Martin G. Sauer http://jci.me/126350

Related CommentaryAdding chimeric antigen receptor–induced killer cells to the medical oncology shelfBrigett D. Brandjes and Marco L. Davila http://jci.me/132536

Posttranscriptional regulator SRSF1 restrains lupus-like T cell activationHyperactive T cells play a key role in orchestrating autoimmune processes in systemic lupus erythematosus (SLE). T cells derived from patients with SLE display decreased expression of the posttranscriptional gene regulator SRSF1, but this protein’s contribution to T cell activity is unclear. When Takayuki Katsuyama and colleagues deleted Srsf1 in T cells, mice developed SLE-like disease and hyperactive T cell phenotypes with enhanced proinflammatory cytokine production. In SLE patient–derived T cells, low SRSF1 expression correlated with decreases in PTEN expression, and in Srsf1-deficient murine T cells, reduced PTEN expression drove increased mTOR pathway activation. mTOR inhibition or PTEN overexpression mitigated proinflammatory cytokine production in the Srsf1-deficient mice. In patient T cells, increasing SRSF1 expression normalized PTEN expression, mTOR signaling, and proinflammatory cytokine production. Together, these findings support SRSF1’s role in controlling the aberrant T cell activation that contributes to SLE-like autoimmunity.

Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunityTakayuki Katsuyama, Hao Li, Denis Comte, George C. Tsokos, and Vaishali R. Moulton http://jci.me/127949

Stress-induced β2-adrenergic signaling promotes immunosuppressive functions in MDSCsChronic stress can worsen cancer progression, metastasis, and treatment outcomes. However, mechanisms underlying stress-induced tumor progression are unclear. New data suggest that β2-adrenergic receptors (β2-ARs) play a role in recruiting myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment and contribute to their persistence and immunosuppressive functions. Hemn Mohammadpour and colleagues demonstrated that stress-induced activation of β2-ARs in MDSCs enhanced tumor growth and metastasis in mice. During chronic stress, β2-AR activation increased MDSC accumulation and persistence in the tumor microenvironment and enhanced MDSC-mediated vascularization. β2-AR signaling also increased the generation of MDSCs from both murine and human peripheral blood cells. Conversely, β2-AR blockade slowed tumor growth and mitigated immunosuppressive functions of MDSCs. In the accompanying Commentary, Ignacio Iñigo-Marco and Marta Alonso highlight the insights into mechanisms by which chronic stress and adrenergic receptor activation can impair antitumor immunity.

β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cellsHemn Mohammadpour, Cameron R. MacDonald, Guanxi Qiao, Minhui Chen, Bowen Dong, Bonnie L. Hylander, Philip L. McCarthy, Scott I. Abrams, and Elizabeth A. Repasky http://jci.me/129502

Related CommentaryDestress and do not suppress: targeting adrenergic signaling in tumor immunosuppressionIgnacio Iñigo-Marco and Marta M. Alonso http://jci.me/133115

immunology

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JCI | Research: Editor’s picks

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

Complement-mediated autoinflammation distinguishes PIGT-defective paroxysmal nocturnal hemoglobinuria

hematology

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic disorder character-ized by complement-mediated hemolysis, thrombosis, and bone marrow failure. The disease is most often linked to somatic mutations in PIGA that impair GPI expression, thereby disrupting the activity of GPI-anchored complement-inhibiting proteins. Britta Höchsmann, Yoshiko Murakami, Makiko Osato, and colleagues describe four patients with PNH driven by PIGT mutations. Each patient harbored a germline mutation in one PIGT allele and a somatic deletion in the other. Though PIGT mutations spared GPI synthesis, they still disrupted GPI anchoring to proteins. Intriguingly, patients presented with autoinflammatory symptoms in addition to typical features of PNH. Using patient leukocytes, the researchers revealed that PIGT defects led to enhanced IL-1β secretion when complement was activated and implicated unanchored GPI in the patients’ autoinflammation. In the accompanying Commentary, Robert Brodsky frames the characterization of this distinct PNH subtype as an important insight into the mechanisms underlying complement-driven inflammation.

Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammationBritta Höchsmann, Yoshiko Murakami, Makiko Osato, Alexej Knaus, Michi Kawamoto, Norimitsu Inoue, Tetsuya Hirata, Shogo Murata, Markus Anliker, Thomas Eggermann, Marten Jäger, Ricarda Floettmann, Alexander Höllein, Sho Murase, Yasutaka Ueda, Jun-ichi Nishimura, Yuzuru Kanakura, Nobuo Kohara, Hubert Schrezenmeier, Peter M. Krawitz, and Taroh Kinoshita http://jci.me/123501

Related Commentary Paroxysmal nocturnal hemoglobinuria without GPI-anchor deficiencyRobert A. Brodsky http://jci.me/131647

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Current research articles

aids/hivHigh-fat diet exacerbates SIV pathogenesis and accelerates disease progressionTianyu He, Cuiling Xu, Noah Krampe, Stephanie M. Dillon, Paola Sette, Elizabeth Falwell, George S. Haret-Richter, Tiffany Butterfield, Tammy L. Dunsmore, William M. McFadden Jr., Kathryn J. Martin, Benjamin B. Policicchio, Kevin D. Raehtz, Ellen P. Penn, Russell P. Tracy, Ruy M. Ribeiro, Daniel N. Frank, Cara C. Wilson, Alan L. Landay, Cristian Apetrei, and Ivona Pandrea (ASCI) http://jci.me/121208

Mechanisms of reactivation of latent tuberculosis infection due to SIV coinfection p. 3Allison N. Bucşan, Ayan Chatterjee, Dhiraj K. Singh, Taylor W. Foreman, Tae-Hyung Lee, Breanna Threeton, Melanie G. Kirkpatrick, Mushtaq Ahmed, Nadia Golden, Xavier Alvarez, James A. Hoxie, Smriti Mehra, Jyothi Rengarajan, Shabaana A. Khader, and Deepak Kaushal http://jci.me/125810

bone biologyHLA-B27–mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitisChin-Hsiu Liu, Sengupta Raj, Chun-Hsiung Chen, Kuo-Hsuan Hung, Chung-Tei Chou, Ing-Ho Chen, Jui-Teng Chien, I-Ying Lin, Shii-Yi Yang, Takashi Angata, Wen-Chan Tsai, James Cheng-Chung Wei, I-Shiang Tzeng, Shih-Chieh Hung, and Kuo-I Lin http://jci.me/125212

Fracture repair requires TrkA signaling by skeletal sensory nervesZhu Li, Carolyn A. Meyers, Leslie Chang, Seungyong Lee, Zhi Li, Ryan Tomlinson, Ahmet Hoke, Thomas L. Clemens, and Aaron W. James http://jci.me/128428

Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodelingShigeki Nishimori, Maureen J. O’Meara, Christian D. Castro, Hiroshi Noda, Murat Cetinbas, Janaina da Silva Martins, Ugur Ayturk, Daniel J. Brooks, Michael Bruce, Mizuki Nagata, Wanida Ono, Christopher J. Janton, Mary L. Bouxsein, Marc Foretz, Rebecca Berdeaux, Ruslan I. Sadreyev, Thomas J. Gardella, Harald Jüppner, Henry M. Kronenberg, and Marc N. Wein http://jci.me/130126

geneticsSlowing ribosome velocity restores folding and function of mutant CFTRKathryn E. Oliver, Robert Rauscher, Marjolein Mijnders, Wei Wang, Matthew J. Wolpert, Jessica Maya, Carleen M. Sabusap, Robert A. Kesterson, Kevin L. Kirk, Andras Rab, Ineke Braakman, Jeong S. Hong, John L. Hartman IV, Zoya Ignatova, and Eric J. Sorscher (ASCI) http://jci.me/124282

Loss-of-function variants in myocardin cause congenital megabladder in humans and miceArjan C. Houweling, Glenda M. Beaman, Alex V. Postma, T. Blair Gainous, Klaske D. Lichtenbelt, Francesco Brancati, Filipa M. Lopes, Ingeborg van der Made, Abeltje M. Polstra, Michael L. Robinson, Kevin D. Wright, Jamie M. Ellingford, Ashley R. Jackson, Eline Overwater, Rita Genesio, Silvio Romano, Letizia Camerota, Emanuela D’Angelo, Elizabeth J. Meijers-Heijboer, Vincent M. Christoffels, Kirk M. McHugh, Brian L. Black, William G. Newman, Adrian S. Woolf, and Esther E. Creemers http://jci.me/128545

hematologyComplement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation p. 6Britta Höchsmann, Yoshiko Murakami, Makiko Osato, Alexej Knaus, Michi Kawamoto, Norimitsu Inoue, Tetsuya Hirata, Shogo Murata, Markus Anliker, Thomas Eggermann, Marten Jäger, Ricarda Floettmann, Alexander Höllein, Sho Murase, Yasutaka Ueda, Jun-ichi Nishimura, Yuzuru Kanakura, Nobuo Kohara, Hubert Schrezenmeier, Peter M. Krawitz, and Taroh Kinoshita http://jci.me/123501

SHP2 inhibition reduces leukemogenesis in models of combined genetic and epigenetic mutationsRuchi Pandey, Baskar Ramdas, Changlin Wan, George Sandusky, Morvarid Mohseni, Chi Zhang, and Reuben Kapur http://jci.me/130520

hepatologyExpression of mitochondrial membrane–linked SAB determines severity of sex-dependent acute liver injurySanda Win, Robert W.M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W.M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, and Neil Kaplowitz (ASCI) http://jci.me/128289

immunologyEndogenous T cells prevent tumor immune escape following adoptive T cell therapyScott R. Walsh, Boris Simovic, Lan Chen, Donald Bastin, Andrew Nguyen, Kyle Stephenson, Talveer S. Mandur, Jonathan L. Bramson, Brian D. Lichty, and Yonghong Wan http://jci.me/126199

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Current research articles

immunologyChimeric antigen receptor–induced BCL11B suppression propagates NK-like cell development p. 5Marcel Maluski, Arnab Ghosh, Jessica Herbst, Vanessa Scholl, Rolf Baumann, Jochen Huehn, Robert Geffers, Johann Meyer, Holger Maul, Britta Eiz-Vesper, Andreas Krueger, Axel Schambach, Marcel R.M. van den Brink, and Martin G. Sauer http://jci.me/126350

Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity p. 5Takayuki Katsuyama, Hao Li, Denis Comte, George C. Tsokos, and Vaishali R. Moulton http://jci.me/127949

Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activityLyra O. Randzavola, Katharina Strege, Marie Juzans, Yukako Asano, Jane C. Stinchcombe, Christian M. Gawden-Bone, Matthew N.J. Seaman, Taco W. Kuijpers, and Gillian M. Griffiths http://jci.me/129388

β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells p. 5Hemn Mohammadpour, Cameron R. MacDonald, Guanxi Qiao, Minhui Chen, Bowen Dong, Bonnie L. Hylander, Philip L. McCarthy, Scott I. Abrams, and Elizabeth A. Repasky http://jci.me/129502

inflammationMaresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functionsNan Chiang, Stephania Libreros, Paul C. Norris, Xavier de la Rosa, and Charles N. Serhan http://jci.me/129448

P2Y6 signaling in alveolar macrophages prevents leukotriene-dependent type 2 allergic lung inflammationJun Nagai, Barbara Balestrieri, Laura B. Fanning, Timothy Kyin, Haley Cirka, Junrui Lin, Marco Idzko, Andreas Zech, Edy Y. Kim, Patrick J. Brennan, and Joshua A. Boyce http://jci.me/129761

metabolismmTORC1 feedback to AKT modulates lysosomal biogenesis through MiT/TFE regulationKaushal Asrani, Sanjana Murali, Brandon Lam, Chan-Hyun Na, Pornima Phatak, Akshay Sood, Harsimar Kaur, Zoya Khan, Michaël Noë, Ravi K. Anchoori, C. Conover Talbot Jr., Barbara Smith, Michael Skaro, and Tamara L. Lotan http://jci.me/128287

Hyperuricemia and gout caused by missense mutation in d-lactate dehydrogenaseMax Drabkin, Yuval Yogev, Lior Zeller, Raz Zarivach, Ran Zalk, Daniel Halperin, Ohad Wormser, Evgenia Gurevich, Daniel Landau, Rotem Kadir, Yonatan Perez, and Ohad S. Birk http://jci.me/129057

Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity p. 4Courtney J. Mercadante, Milankumar Prajapati, Heather L. Conboy, Miriam E. Dash, Carolina Herrera, Michael A. Pettiglio, Layra Cintron-Rivera, Madeleine A. Salesky, Deepa B. Rao, and Thomas B. Bartnikas http://jci.me/129710

Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in mice p. 4Zhuzhen Zhang, Mengle Shao, Chelsea Hepler, Zhenzhen Zi, Shangang Zhao, Yu A. An, Yi Zhu, Alexandra Ghaben, May-yun Wang, Na Li, Toshiharu Onodera, Nolwenn Joffin, Clair Crewe, Qingzhang Zhu, Lavanya Vishvanath, Ashwani Kumar, Chao Xing, Qiong A. Wang, Laurent Gautron, Yingfeng Deng, Ruth Gordillo, Ilja Kruglikov, Christine M. Kusminski, Rana K. Gupta, and Philipp E. Scherer http://jci.me/130239

nephrologyFOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injuryMonica Chang-Panesso, Farid F. Kadyrov, Matthew Lalli, Haojia Wu, Shiyo Ikeda, Eirini Kefaloyianni, Mai M. Abdelmageed, Andreas Herrlich, Akio Kobayashi, and Benjamin D. Humphreys (ASCI) http://jci.me/125519

neuroscienceSchwann cells expressing nociceptive channel TRPA1 orchestrate ethanol-evoked neuropathic pain in miceFrancesco De Logu, Simone Li Puma, Lorenzo Landini, Francesca Portelli, Alessandro Innocenti, Daniel Souza Monteiro de Araujo, Malvin N. Janal, Riccardo Patacchini, Nigel W. Bunnett, Pierangelo Geppetti, and Romina Nassini http://jci.me/128022

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Sonic Hedgehog repression underlies gigaxonin mutation–induced motor deficits in giant axonal neuropathyYoan Arribat, Karolina S. Mysiak, Léa Lescouzères, Alexia Boizot, Maxime Ruiz, Mireille Rossel, and Pascale Bomont http://jci.me/129788

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model miceBin Gu, Manhua Zhu, Madison R. Glass, Marie Rougié, Viktoriya D. Nikolova, Sheryl S. Moy, Paul R. Carney, and Benjamin D. Philpot http://jci.me/130419

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse modelsKathryn H. Morelli, Laurie B. Griffin, Nettie K. Pyne, Lindsay M. Wallace, Allison M. Fowler, Stephanie N. Oprescu, Ryuichi Takase, Na Wei, Rebecca Meyer-Schuman, Dattatreya Mellacheruvu, Jacob O. Kitzman, Samuel G. Kocen, Timothy J. Hines, Emily L. Spaulding, James R. Lupski, Alexey Nesvizhskii, Pedro Mancias, Ian J. Butler, Xiang-Lei Yang, Ya-Ming Hou, Anthony Antonellis, Scott Q. Harper, and Robert W. Burgess http://jci.me/130600

oncologyA-to-I–edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosisXiaoyan Xu, Yumeng Wang, Kamalika Mojumdar, Zhicheng Zhou, Kang Jin Jeong, Lingegowda S. Mangala, Shuangxing Yu, Yiu Huen Tsang, Cristian Rodriguez-Aguayo, Yiling Lu, Gabriel Lopez-Berestein, Anil K. Sood, Gordon B. Mills, and Han Liang http://jci.me/123396

CCL28-induced RARβ expression inhibits oral squamous cell carcinoma bone invasionJunhee Park, Xianglan Zhang, Sun Kyoung Lee, Na-Young Song, Seung Hwa Son, Ki Rim Kim, Jae Hoon Shim, Kwang-Kyun Park, and Won-Yoon Chung http://jci.me/125336

Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune responseMahnaz Sahraei, Balkrishna Chaube, Yuting Liu, Jonathan Sun, Alanna Kaplan, Nathan L. Price, Wen Ding, Stanley Oyaghire, Rolando García-Milian, Sameet Mehta, Yana K. Reshetnyak, Raman Bahal, Paolo Fiorina, Peter M. Glazer, David L. Rimm, Carlos Fernández-Hernando, and Yajaira Suárez http://jci.me/127125

Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development p. 2Peng Tan, Lian He, Changsheng Xing, Jingrong Mao, Xiao Yu, Motao Zhu, Lixia Diao, Leng Han, Yubin Zhou, James M. You, Helen Y. Wang, and Rong-Fu Wang http://jci.me/127721

Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitmentAmy J. Petty, Ang Li, Xinyi Wang, Rui Dai, Benjamin Heyman, David Hsu, Xiaopei Huang, and Yiping Yang (ASCI) http://jci.me/128644

Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance p. 3Dhanya K. Nambiar, Todd Aguilera, Hongbin Cao, Shirley Kwok, Christina Kong, Joshua Bloomstein, Zemin Wang, Vangipuram S. Rangan, Dadi Jiang, Rie von Eyben, Rachel Liang, Sonya Agarwal, A. Dimitrios Colevas, Alan Korman, Clint T. Allen, Ravindra Uppaluri, Albert C. Koong, Amato Giaccia, and Quynh Thu Le http://jci.me/129025

ophthalmologyCaspase-8 modulates physiological and pathological angiogenesis during retina developmentNathalie Tisch, Aida Freire-Valls, Rosario Yerbes, Isidora Paredes, Silvia La Porta, Xiaohong Wang, Rosa Martín-Pérez, Laura Castro, Wendy Wei-Lynn Wong, Leigh Coultas, Boris Strilic, Hermann-Josef Gröne, Thomas Hielscher, Carolin Mogler, Ralf H. Adams, Peter Heiduschka, Lena Claesson-Welsh, Massimiliano Mazzone, Abelardo López-Rivas, Thomas Schmidt, Hellmut G. Augustin, and Carmen Ruiz de Almodovar http://jci.me/122767

Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurityJiong Hu, Sofia-Iris Bibli, Janina Wittig, Sven Zukunft, Jihong Lin, Hans-Peter Hammes, Rüdiger Popp, and Ingrid Fleming http://jci.me/123835

vascular biologyHemodynamic regulation of perivalvular endothelial gene expression prevents deep venous thrombosisJohn D. Welsh, Mark H. Hoofnagle, Sharika Bamezai, Michael Oxendine, Lillian Lim, Joshua D. Hall, Jisheng Yang, Susan Schultz, James Douglas Engel, Tsutomu Kume, Guillermo Oliver, Juan M. Jimenez, and Mark L. Kahn (ASCI) http://jci.me/124791

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm p. 2Michael Hugelshofer, Raphael M. Buzzi, Christian A. Schaer, Henning Richter, Kevin Akeret, Vania Anagnostakou, Leila Mahmoudi, Raphael Vaccani, Florence Vallelian, Jeremy W. Deuel, Peter W. Kronen, Zsolt Kulcsar, Luca Regli, Jin Hyen Baek, Ivan S. Pires, Andre F. Palmer, Matthias Dennler, Rok Humar, Paul W. Buehler, Patrick R. Kircher, Emanuela Keller, and Dominik J. Schaer http://jci.me/130630

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jci.org/this-month

Predicting type 2 diabetic kidney disease progression in American Indians 11

Anti–IL-33 has potential for desensitizing peanut-allergic patients 12

Dectin-1 deficiency linked to lung graft dysfunction 12

Humanized mice allow comparison of Ebola and Reston virus infection 13

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

December 2019

Sonic hedgehog signals for glomerulosclerosis p. 11

This Month

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Pilar Alcaide

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Yuan Chang

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Kang Chen

Zhou-Feng Chen

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Mathias Lichterfeld

Rodger A. Liddle

André Lieber

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Mark Nicolls

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

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This MonthDecember 2019

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JCI Insight’s first Impact Factor: 6.014Read more about JCI Insight’s Impact Factor, reported in the 2018 Journal Citation Reports (June 2019): http://jci.me/muhtx

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and chromatin remodeling proteins control gene transcription and nucleosome remodeling, thereby influencing key signaling and developmental pathways. Dr. Martin is a member of the American Society for Clinical Investigation, serving as Councilor 2017–2020.

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Yao H, Hill SF, Skidmore JM, Sperry ED, Swiderski DL, Sanchez GJ, Bartels CF, Raphael Y, Scacheri PC, Iwase S, Martin DM. CHD7 represses the retinoic acid synthesis enzyme ALDH1A3 during inner ear development. JCI Insight. 2018;3(4):97440.

Ziats MN, Ahmad A, Bernat JA, Fisher R, Glassford M, Hannibal MC, Jacher JE, Weiser N, Keegan CE, Lee KN, Marzulla TB, O’Connor BC, Quinonez SC, Seemann L, Turner L, Bielas S, Harris NL, Ogle JD, Innis JW, Martin DM. Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing [published online ahead of print October 16, 2019]. Pediatr Res. doi: 10.1038/s41390-019-0611-5.

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Editor’s picks

on the jci insight cover nephrology

Podocyte-derived sonic hedgehog serves as a messenger for mesangial cell activationProteinuria and glomerulosclerosis are characteristic of glomerular disease that often progresses to renal failure. Podocyte injury underlies proteinuria, while mesangial cell activation promotes glomerular sclerosis; however, it is not clear whether there is a direct link among podocyte injury, mesangial cell activation, and subsequent glomerulosclerosis. Dong Zhou and colleagues determined that sonic hedgehog (Shh) expression increases in podocytes after injury and that podocyte-derived Shh promotes mesangial cell activation. In murine models, podocyte-specific Shh deficiency or pharmacological Shh inhibition had no effect on proteinuria but attenuated mesangial cell activation and glomerulosclerosis. Moreover, in patients with chronic kidney disease, Shh was upregulated in podocytes, and high circulating levels of this ligand associated with glomerulo-sclerosis but not proteinuria. Together, these results support Shh as a critical mediator of podocyte–mesangial cell crosstalk. The cover image shows podocyte-specific staining of Shh (red) in a kidney biopsy from a patient with membranous nephritis.

Sonic hedgehog connects podocyte injury to mesangial activation and glomerulosclerosisDong Zhou, Haiyan Fu, Yang Han, Lu Zhang, Shijia Liu, Lin Lin, Donna B. Stolz, and Youhua Liu http://jci.me/130515

Lipid biomarkers predict diabetic kidney disease progression in American IndiansDiabetes is the leading cause of end-stage kidney disease, but traditional biomarkers of kidney function have limited value in predicting diabetic kidney disease (DKD) progression. To identify lipidomic predictors of early progression of DKD and enable risk stratification and more targeted intervention, Farsad Afshinnia and colleagues performed a longitudinal study of American Indians with type 2 diabetes. Measurement of over 400 lipid species revealed that those who progressed to DKD had higher levels of polyunsaturated triacylglycerols and lower levels of C16–C20 acylcarni-tines. Renal transcriptomic analysis confirmed that these lipid phenotypes resulted from enhanced lipogenesis and impaired mitochondrial β-oxida-tion, in particular the activation of acetyl-CoA carboxylase. These results

reveal lipidomic markers that may be used to predict DKD risk and highlight a potential molecular mechanism that underlies those changes.

Increased lipogenesis and impaired β-oxidation predict type 2 diabetic kidney disease progression in American IndiansFarsad Afshinnia, Viji Nair, Jiahe Lin, Thekkelnaycke M. Rajendiran, Tanu Soni, Jaeman Byun, Kumar Sharma, Patrice E. Fort, Thomas W. Gardner, Helen C. Looker, Robert G. Nelson, Frank C. Brosius, Eva L. Feldman, George Michailidis, Matthias Kretzler, and Subramaniam Pennathur http://jci.me/130317

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JCI Insight | Editor’s picks

12

immunology

neuroscience

Dectin-1 polymorphism linked to poor outcome in lung graft recipientsLung transplant recipients experience relatively low survival rates compared with recipients of other solid organ transplants, and more than 50% of all recipients who survive 5 years experience chronic lung allograft dysfunction. Risk of allograft dysfunction is increased following airway infections, indicating a key role for the innate immune system. The innate immune receptor dectin-1 activates cytokine signaling in response to pathogen stimulation, and patients who are homozygous for a dectin-1 truncation mutant, Y238X, exhibit impaired recognition of fungal pathogens. Therefore, Daniel Calabrese and colleagues assessed the prevalence of the Y238X polymorphism in two cohorts of lung allograft recipients. Carriers of the variant exhibited lower levels of dectin-1 expression, which was associated with higher fungal pathogen burden, increased risk of graft dysfunction, and increased mortality. These findings indicate that reduced levels of dectin-1 may impair pathogen recognition, which, in the setting of immunosuppression, increases risk of graft dysfunction and death.

Dectin-1 genetic deficiency predicts chronic lung allograft dysfunction and deathDaniel R. Calabrese, Ping Wang, Tiffany Chong, Jonathan Hoover, Jonathan P. Singer, Dara Torgerson, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Jason D. Christie, LTOG investigators, and John R. Greenland http://jci.me/133083

Phase 2a study of anti–IL-33 shows promise for peanut allergyEpithelial-derived cytokines, including IL-33, are thought to mediate atopic diseases, such as food allergy, asthma, and atopic dermatitis. Indeed, anti–IL-33 treatments have shown promise in preclinical studies for atopic dermatitis, and multiple clinical trials targeting this pathway are underway. Sharon Chinthrajah and colleagues performed a small phase 2a clinical trial of an anti–IL-33 antibody (etokimab) in adults with peanut allergy. Patients were exposed to a standardized oral food challenge 15 and 45 days after a single dose of etokimab. The antibody was well tolerated, and on day 15, 75% of etokimab-treated patients tolerated an oral challenge of peanut protein, compared with 0% of the placebo group. At this early time point, etokimab treatment also decreased levels of peanut-specific IgE, the numbers of peanut-specific CD4+ T cells, and the levels of several inflammatory cytokines. This work indicates the potential of targeting IL-33 for desensitizing peanut-allergic patients; further larger studies are needed to confirm these pilot results.

Phase 2a randomized, placebo-controlled study of anti–IL-33 in peanut allergySharon Chinthrajah, Shu Cao, Cherie Liu, Shu-Chen Lyu, Sayantani B. Sindher, Andrew Long, Vanitha Sampath, Daniel Petroni, Marco Londei, and Kari C. Nadeau (ASCI) http://jci.me/131347

Network abnormalities appear before overt lysosomal storage disorder symptomsLysosomal storage disorders (LSDs) result from mutations that alter the function of lysosomal enzymes. However, two-thirds of LSD patients experience neurological symptoms that are not alleviated by enzymatic replacement therapy. CLN3 disease is one such LSD that causes childhood dementia, but how the loss of CLN3 protein function causes neuronal dysfunction was unclear. Rebecca Ahrens-Nicklas and colleagues used electrophysiology and voltage-sensitive imaging techniques to probe neuronal and

network dysfunction in 2 mouse models of CLN3. CLN3 disease mice displayed progressive network abnormalities in the hippocampus before the onset of behavioral phenotypes and neuron loss. CLN3 disease mice also displayed EEG abnormali-ties, including changes in the number of sharp-wave ripples, which are known to be important for memory consolidation and are also disrupted in Alzheimer’s disease. This suggests that different forms of dementia may result from common changes to neural networks and

emphasizes the need to develop interventions that target neuronal circuit defects.

Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorderRebecca C. Ahrens-Nicklas, Luis Tecedor, Arron F. Hall, Elena Lysenko, Akiva S. Cohen, Beverly L. Davidson, and Eric D. Marsh http://jci.me/131961

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JCI Insight | Editor’s picks

infectious diseaseautoimmunity

PAD2-mediated citrullination differentially regulates Th2 and Th17 cells

Humanized mice recapitulate clinal differences between Ebola and Reston virusThe six species of Ebolavirus exhibit a broad range of pathogenicity. At the extremes, Ebola virus (Zaire ebolavirus, EBOV) has a 90% case fatality rate, while Reston virus (Reston ebolavirus, RESTV) is believed to be nonpathogenic in humans. Nonhuman primates (NHPs) are a preferred model to study virus pathogenicity and vaccine development; however, NHPs are particularly susceptible to RESTV, complicating comparative studies. Beatriz Escudero-Pérez and colleagues utilized a humanized mouse model to compare EBOV and RESTV pathogenesis. In this model, EBOV was markedly more pathogenic than RESTV, rapidly replicating in the lungs of infected mice (see the accompanying image) and recapitulating the approximately 90% lethality rate observed in humans. Interestingly, RESTV resulted in death of approximately 20% of infected mice, associated with high levels of inflammation and viral replication in the liver. These results indicate that the humanized mouse model may be useful for testing pathogenicity of emerging viruses, and reveal potential dangers of RESTV infection in susceptible patients.

Comparative pathogenesis of Ebola virus and Reston virus infection in humanized miceBeatriz Escudero-Pérez, Paula Ruibal, Monika Rottstegge, Anja Lüdtke, Julia R. Port, Kristin Hartmann, Sergio Gómez-Medina, Jürgen Müller-Guhl, Emily V. Nelson, Susanne Krasemann, Estefanía Rodríguez, and César Muñoz-Fontela http://jci.me/126070

Citrullination is a posttranslational protein modification mediated by peptidylarginine deiminases (PADs). Aberrant citrullination contributes to diseases, including rheumatoid arthritis, and inhibition of PAD enzymes is beneficial in models of inflammatory diseases. However, the role of PAD enzymes in adaptive immune cells is poorly understood. To investigate the effect of citrullination on Th cell differentia-tion, Bo Sun, Hui-Hsin Chang, and colleagues evaluated a pan-PAD inhibitor in primary human Th cells. Blocking citrullination attenuated the differentiation of human primary Th17 cells but promoted the differentiation of Th2 cells, and this effect was recapitulated in mouse cells with PAD2 deficiency. PAD2 citrullinated the Th2-specific tran-scription factor GATA3, thereby attenuating DNA binding activity. Reciprocally, PAD2-mediated citrullination of RORγt, the key transcription factor driving Th17 differentiation, augmented its ability to bind to DNA. Furthermore, PAD2-deficient mice exhibited altered Th2 and Th17 immune responses and sensitivity to allergic airway inflammation, highlighting the potential caveats of targeting PAD2 in Th-mediated disease.

Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullinationBo Sun, Hui-Hsin Chang, Ari Salinger, Beverly Tomita, Mandar Bawadekar, Caitlyn L. Holmes, Miriam A. Shelef, Eranthie Weerapana, Paul R. Thompson, and I-Cheng Ho (ASCI) http://jci.me/129687

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Current articleseIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancerDavid Müller, Sauyeun Shin, Théo Goullet de Rugy, Rémi Samain, Romain Baer, Manon Strehaiano, Laia Masvidal-Sanz, Julie Guillermet-Guibert, Christine Jean, Yoshinori Tsukumo, Nahum Sonenberg, Frédéric Marion, Nicolas Guilbaud, Jean-Sébastien Hoffmann, Ola Larsson, Corinne Bousquet, Stéphane Pyronnet, and Yvan Martineau http://jci.me/121951

iPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human isletsYi-Ju Chen, Taiji Yamazoe, Karla F. Leavens, Fabian L. Cardenas-Diaz, Andrei Georgescu, Dongeun Huh, Paul Gadue, and Ben Z. Stanger (ASCI) http://jci.me/124644

NK cell defects in X-linked pigmentary reticulate disorderPetro Starokadomskyy, Katelynn M. Wilton, Konrad Krzewski, Adam Lopez, Luis Sifuentes-Dominguez, Brittany Overlee, Qing Chen, Ann Ray, Aleksandra Gil-Krzewska, Mary Peterson, Lisa N. Kinch, Luis Rohena, Eyal Grunebaum, Andrew R. Zinn, Nick V. Grishin, Daniel D. Billadeau, and Ezra Burstein (ASCI) http://jci.me/125688

Comparative pathogenesis of Ebola virus and Reston virus infection in humanized mice p. 13Beatriz Escudero-Pérez, Paula Ruibal, Monika Rottstegge, Anja Lüdtke, Julia R. Port, Kristin Hartmann, Sergio Gómez-Medina, Jürgen Müller-Guhl, Emily V. Nelson, Susanne Krasemann, Estefanía Rodríguez, and César Muñoz-Fontela http://jci.me/126070

Transition to 37°C reveals importance of NADPH in mitigating oxidative stress in stored RBCsAline Roch, Nicholas J. Magon, Jessica Maire, Cacang Suarna, Anita Ayer, Sophie Waldvogel, Beat A. Imhof, Mark J. Koury, Roland Stocker, and Marc Schapira http://jci.me/126376

TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagyAli Javaheri, Geetika Bajpai, Antonino Picataggi, Smrithi Mani, Layla Foroughi, Hosannah Evie, Attila Kovacs, Carla J. Weinheimer, Krzystztof Hyrc, Qingli Xiao, Andrea Ballabio, Jin-Moo Lee, Scot J. Matkovich, Babak Razani, Joel D. Schilling, Kory J. Lavine, and Abhinav Diwan (ASCI) http://jci.me/127312

O-GlcNAc transferase suppresses necroptosis and liver fibrosisBichen Zhang, Min-Dian Li, Ruonan Yin, Yuyang Liu, Yunfan Yang, Kisha A. Mitchell-Richards, Jin Hyun Nam, Rui Li, Li Wang, Yasuko Iwakiri, Dongjun Chung, Marie E. Robert, Barbara E. Ehrlich, Anton M. Bennett, Jun Yu, Michael H. Nathanson, and Xiaoyong Yang http://jci.me/127709

Athletes feature greater rates of muscle glucose transport and glycogen synthesis during lipid infusionEsther Phielix, Paul Begovatz, Sofiya Gancheva, Alessandra Bierwagen, Esther Kornips, Gert Schaart, Matthijs K. C. Hesselink, Patrick Schrauwen, and Michael Roden http://jci.me/127928

Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypesNahal Mansouri, Gareth R. Willis, Angeles Fernandez-Gonzalez, Monica Reis, Sina Nassiri, S. Alex Mitsialis, and Stella Kourembanas (ASCI) http://jci.me/128060

Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancerLouise A. Koopman, Mikkel G. Terp, Gijs G. Zom, Maarten L. Janmaat, Kirstine Jacobsen, Elke Gresnigt-van den Heuvel, Marcel Brandhorst, Ulf Forssmann, Freddy de Bree, Nora Pencheva, Andreas Lingnau, Maria A. Zipeto, Paul W.H.I. Parren, Esther C.W. Breij, and Henrik J. Ditzel (ASCI) http://jci.me/128199

IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammationMatthew S. Godwin, Kristen M. Reeder, Jaleesa M. Garth, Jonathan P. Blackburn, MaryJane Jones, Zhihong Yu, Sadis Matalon, Annette T. Hastie, Deborah A. Meyers, and Chad Steele http://jci.me/129055

Progenitor cell combination normalizes retinal vascular development in the oxygen-induced retinopathy (OIR) modelSergio Li Calzi, Lynn C. Shaw, Leni Moldovan, William C. Shelley, Xiaoping Qi, Lyne Racette, Judith L. Quigley, Seth D. Fortmann, Michael E. Boulton, Mervin C. Yoder, and Maria B. Grant http://jci.me/129224

MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophagesJihane Khalife, Jayeeta Ghose, Marianna Martella, Domenico Viola, Alberto Rocci, Estelle Troadec, Cesar Terrazas, Abhay R. Satoskar, Emine Gulsen Gunes, Ada Dona, James F. Sanchez, P. Leif Bergsagel, Marta Chesi, Alex Pozhitkov, Steven Rosen, Guido Marcucci, Jonathan J. Keats, Craig C. Hofmeister, Amrita Krishnan, Enrico Caserta, and Flavia Pichiorri http://jci.me/129348

Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responsesSanjay Ranjit, Jian Yao Wong, Jia W. Tan, Chee Sin Tay, Jessica M. Lee, Kelly Yin Han Wong, Luminita H. Pojoga, Danielle L. Brooks, Amanda E. Garza, Stephen A. Maris, Isis Akemi Katayama, Jonathan S. Williams, Alicia Rivera, Gail K. Adler, Gordon H. Williams, and Jose R. Romero http://jci.me/129615

OX40 expression in neutrophils promotes hepatic ischemia/reperfusion injuryHua Jin, Chunpan Zhang, Chengyang Sun, Xinyan Zhao, Dan Tian, Wen Shi, Yue Tian, Kai Liu, Guangyong Sun, Hufeng Xu, and Dong Zhang http://jci.me/129736

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Current articles

Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformationsKaitlyn Zenner, Chi Vicky Cheng, Dana M. Jensen, Andrew E. Timms, Giridhar Shivaram, Randall Bly, Sheila Ganti, Kathryn B. Whitlock, William B. Dobyns, Jonathan Perkins, and James T. Bennett http://jci.me/129884

Increased lipogenesis and impaired β-oxidation predict type 2 diabetic kidney disease progression in American Indians p. 11Farsad Afshinnia, Viji Nair, Jiahe Lin, Thekkelnaycke M. Rajendiran, Tanu Soni, Jaeman Byun, Kumar Sharma, Patrice E. Fort, Thomas W. Gardner, Helen C. Looker, Robert G. Nelson, Frank C. Brosius, Eva L. Feldman, George Michailidis, Matthias Kretzler, and Subramaniam Pennathur http://jci.me/130317

Multiple cancer-specific antigens are targeted by a chimeric antibody receptor on a single cancer cellYanran He, Karin Schreiber, Steven P. Wolf, Frank Wen, Catharina Steentoft, Jonathan Zerweck, Madeline Steiner, Preeti Sharma, H. Michael Shepard, Avery Posey, Carl H. June, Ulla Mandel, Henrik Clausen, Matthias Leisegang, Stephen C. Meredith, David M. Kranz, and Hans Schreiber http://jci.me/130416

Salt increases monocyte CCR2 expression and inflammatory responses in humansEliane F.E. Wenstedt, Sanne G.S. Verberk, Jeffrey Kroon, Annette E. Neele, Jeroen Baardman, Nike Claessen, Özge T. Pasaoglu, Emma Rademaker, Esmee M. Schrooten, Rosa D. Wouda, Menno P.J. de Winther, Jan Aten, Liffert Vogt, and Jan Van den Bossche http://jci.me/130508

YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinomaBo Tu, Jun Yao, Sammy Ferri-Borgogno, Jun Zhao, Shujuan Chen, Qiuyun Wang, Liang Yan, Xin Zhou, Cihui Zhu, Seungmin Bang, Qing Chang, Christopher A. Bristow, Ya’an Kang, Hongwu Zheng, Huamin Wang, Jason B. Fleming, Michael Kim, Timothy P. Heffernan, Giulio F. Draetta, Duojia Pan, Anirban Maitra, Wantong Yao, Sonal Gupta, and Haoqiang Ying http://jci.me/130811

VEGF188 promotes corneal reinnervation after injuryJames T. Brash, Laura Denti, Christiana Ruhrberg, and Franziska Bucher http://jci.me/130979

A20 as an immune tolerance factor can determine islet transplant outcomesNathan W. Zammit, Stacey N. Walters, Karen L. Seeberger, Philip J. O’Connell, Gregory S. Korbutt, and Shane T. Grey http://jci.me/131028

Soluble Thy-1 reverses lung fibrosis via its integrin-binding motifChunting Tan, Min Jiang, Simon S. Wong, Celia R. Espinoza, Ceonne Kim, Xiaoping Li, Edward Connors, and James S. Hagood http://jci.me/131152

Haptoglobin-2 variant increases susceptibility to acute respiratory distress syndrome during sepsisV. Eric Kerchberger, Julie A. Bastarache, Ciara M. Shaver, Hiromasa Nagata, J. Brennan McNeil, Stuart R. Landstreet, Nathan D. Putz, Wen-Kuang Yu, Jordan Jesse, Nancy E. Wickersham, Tatiana N. Sidorova, David R. Janz, Chirag R. Parikh, Edward D. Siew, and Lorraine B. Ware (ASCI) http://jci.me/131206

Effects of rosuvastatin on the immune system in healthy volunteers with normal serum cholesterolPeer W.F. Karmaus, Min Shi, Shira Perl, Angélique Biancotto, Julián Candia, Foo Cheung, Yuri Kotliarov, Neal Young, Michael B. Fessler (ASCI), and the CHI Consortium http://jci.me/131530

Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder p. 12Rebecca C. Ahrens-Nicklas, Luis Tecedor, Arron F. Hall, Elena Lysenko, Akiva S. Cohen, Beverly L. Davidson, and Eric D. Marsh http://jci.me/131961

Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotidesKentaro Fujii, Akiko Kubo, Kazutoshi Miyashita, Masaaki Sato, Aika Hagiwara, Hiroyuki Inoue, Masaki Ryuzaki, Masanori Tamaki, Takako Hishiki, Noriyo Hayakawa, Yasuaki Kabe, Hiroshi Itoh, and Makoto Suematsu http://jci.me/124816

Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathiesDaniel Brayson, Andrea Frustaci, Romina Verardo, Cristina Chimenti, Matteo Antonio Russo, Robert Hayward, Sadia Munir Ahmad, Gema Vizcay-Barrena, Andrea Protti, Peter S. Zammit, Cristobal G. dos Remedios, Elisabeth Ehler, Ajay M. Shah, and Catherine M. Shanahan http://jci.me/126315

2B4 but not PD-1 blockade improves mortality in septic animals with preexisting malignancyChing-wen Chen, Ming Xue, Wenxiao Zhang, Jianfeng Xie, Craig M. Coopersmith, and Mandy L. Ford http://jci.me/127867

Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastomaRan Wei, Xiang Ren, Hongyu Kong, Zhongping Lv, Yongjiang Chen, Yunjing Tang, Yujiao Wang, Lirong Xiao, Tao Yu, Sabiha Hacibekiroglu, Chen Liang, Andras Nagy, Rod Bremner, and Danian Chen http://jci.me/127889

The small molecule Chicago Sky Blue promotes heart repair following myocardial infarction in miceOren Yifa, Karen Weisinger, Elad Bassat, Hanjun Li, David Kain, Haim Barr, Noga Kozer, Alexander Genzelinakh, Dana Rajchman, Tamar Eigler, Kfir Baruch Umansky, Daria Lendengolts, Ori Brener, Nenad Bursac, and Eldad Tzahor http://jci.me/128025

Continuous vestibular implant stimulation partially restores eye-stabilizing reflexesPeter J. Boutros, Desi P. Schoo, Mehdi Rahman, Nicolas S. Valentin, Margaret R. Chow, Andrianna I. Ayiotis, Brian J. Morris, Andreas Hofner, Aitor Morillo Rascon, Andreas Marx, Ross Deas, Gene Y. Fridman, Natan S. Davidovics, Bryan K. Ward, Carolina Treviño, Stephen P. Bowditch, Dale C. Roberts, Kelly E. Lane, Yoav Gimmon, Michael C. Schubert, John P. Carey, Andreas Jaeger, and Charles C. Della Santina http://jci.me/128397

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Investigation of a dilated cardiomyopathy–associated variant in BAG3 using genome-edited iPSC-derived cardiomyocytesChris McDermott-Roe, Wenjian Lv, Tania Maximova, Shogo Wada, John Bukowy, Maribel Marquez, Shuping Lai, Amarda Shehu, Ivor Benjamin, Aron Geurts, and Kiran Musunuru (ASCI) http://jci.me/128799

TSLP protects against liver I/R injury via activation of the PI3K/Akt pathwayShilai Li, Zhongjie Yi, Meihong Deng, Melanie J. Scott, Chenxuan Yang, Wenbo Li, Zhao Lei, Nicole M. Santerre, Patricia Loughran, and Timothy R. Billiar (ASCI) http://jci.me/129013

Hemagglutinin head-specific responses dominate over stem-specific responses following prime boost with mismatched vaccinesSinthujan Jegaskanda, Sarah F. Andrews, Adam K. Wheatley, Jonathan W. Yewdell, Adrian B. McDermott, and Kanta Subbarao http://jci.me/129035

Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination p. 13Bo Sun, Hui-Hsin Chang, Ari Salinger, Beverly Tomita, Mandar Bawadekar, Caitlyn L. Holmes, Miriam A. Shelef, Eranthie Weerapana, Paul R. Thompson, and I-Cheng Ho (ASCI) http://jci.me/129687

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemiaAlessandro Matte, Enrica Federti, Michael Winter, Annette Koerner, Anja Harmeier, Norman Mazer, Tomas Tomka, Maria Luisa Di Paolo, Luigia Defalco, Immacolata Andolfo, Elisabetta Beneduce, Achille Iolascon, Alejandra Macias-Garcia, Jane-Jane Chen, Anne Janin, Christhophe Lebouef, Franco Turrini, Carlo Brugnara (ASCI), and Lucia De Franceschi http://jci.me/130111

Sonic hedgehog connects podocyte injury to mesangial activation and glomerulosclerosis p. 11Dong Zhou, Haiyan Fu, Yang Han, Lu Zhang, Shijia Liu, Lin Lin, Donna B. Stolz, and Youhua Liu http://jci.me/130515

Genome-wide suppressor screen identifies USP35/USP38 as therapeutic candidates for ciliopathiesI-Chun Tsai, Kevin A. Adams, Joyce A. Tzeng, Omar Shennib, Perciliz L. Tan, and Nicholas Katsanis http://jci.me/130516

Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cellsDavid M. Peereboom, Tyler J. Alban, Matthew M. Grabowski, Alvaro G. Alvarado, Balint Otvos, Defne Bayik, Gustavo Roversi, Mary McGraw, Pengjing Huang, Alireza M. Mohammadi, Harley I. Kornblum, Tomas Radivoyevitch, Manmeet S. Ahluwalia, Michael A. Vogelbaum, and Justin D. Lathia http://jci.me/130748

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammationSebastian Lorscheid, Anne Müller, Jessica Löffler, Claudia Resch, Philip Bucher, Florian C. Kurschus, Ari Waisman, Knut Schäkel, Stephan Hailfinger, Klaus Schulze-Osthoff, and Daniela Kramer http://jci.me/130835

Transcriptional heterogeneity of fibroblasts is a hallmark of the aging heartRamon Vidal, Julian Uwe Gabriel Wagner, Caroline Braeuning, Cornelius Fischer, Ralph Patrick, Lukas Tombor, Marion Muhly-Reinholz, David John, Magdalena Kliem, Thomas Conrad, Nuno Guimarães-Camboa, Richard Harvey, Stefanie Dimmeler, and Sascha Sauer http://jci.me/131092

Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosisNathan L. Price, Verónica Miguel, Wen Ding, Abhishek K. Singh, Shipra Malik, Noemi Rotllan, Anna Moshnikova, Jakub Toczek, Caroline Zeiss, Mehran M. Sadeghi, Noemi Arias, Ángel Baldán, Oleg A. Andreev, Diego Rodríguez-Puyol, Raman Bahal, Yana K. Reshetnyak, Yajaira Suárez, Carlos Fernández-Hernando, and Santiago Lamas http://jci.me/131102

Phase 2a randomized, placebo-controlled study of anti–IL-33 in peanut allergy p. 12Sharon Chinthrajah, Shu Cao, Cherie Liu, Shu-Chen Lyu, Sayantani B. Sindher, Andrew Long, Vanitha Sampath, Daniel Petroni, Marco Londei, and Kari C. Nadeau (ASCI) http://jci.me/131347

Transcriptional regulatory model of fibrosis progression in the human lungJohn E. McDonough, Farida Ahangari, Qin Li, Siddhartha Jain, Stijn E. Verleden, Jose Herazo-Maya, Milica Vukmirovic, Giuseppe DeIuliis, Argyrios Tzouvelekis, Naoya Tanabe, Fanny Chu, Xiting Yan, Johny Verschakelen, Robert J. Homer, Dimitris V. Manatakis, Junke Zhang, Jun Ding, Karen Maes, Laurens De Sadeleer, Robin Vos, Arne Neyrinck, Panayiotis V. Benos, Ziv Bar-Joseph, Dean Tantin, James C. Hogg, Bart M. Vanaudenaerde, Wim A. Wuyts, and Naftali Kaminski http://jci.me/131597

Using a barcoded AAV capsid library to select for clinically relevant gene therapy vectorsKatja Pekrun, Gustavo De Alencastro, Qing-Jun Luo, Jun Liu, Youngjin Kim, Sean Nygaard, Feorillo Galivo, Feijie Zhang, Ren Song, Matthew R. Tiffany, Jianpeng Xu, Matthias Hebrok, Markus Grompe, and Mark A. Kay (ASCI) http://jci.me/131610

Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in miceYishu Wang, Qinnan Yan, Yiran Zhao, Xin Liu, Simin Lin, Peijun Zhang, Liting Ma, Yumei Lai, Xiaochun Bai, Chuanju Liu, Chuanyue Wu, Jian Q. Feng, Di Chen, Huiling Cao, and Guozhi Xiao http://jci.me/131692

Dectin-1 genetic deficiency predicts chronic lung allograft dysfunction and death p. 12Daniel R. Calabrese, Ping Wang, Tiffany Chong, Jonathan Hoover, Jonathan P. Singer, Dara Torgerson, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Jason D. Christie, LTOG investigators, and John R. Greenland http://jci.me/133083

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