Post on 13-Mar-2020
jci.org/this-month
GIP receptors relay the gut-brain response to overnutrition 3
PAHSAs protect β cells from autoimmune attack 4
The fecal metabolome tattles on C. difficile infection 5
Adding NK cells to the immunotherapy armament 6
JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
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September 2019
Immunosuppressive effects of tumor-intrinsic EPHA2 expression p. 2
This Month
Journal of Clinical Investigation Consulting Editors
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Luc Van Kaer
David M. Virshup
Matthias von Herrath
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Yisong Y. Wan
Bart O. Williams
Allan W. Wolkoff
Joseph C. Wu
Thomas A. Wynn
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Mingzhao Xing
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Srinivasan Yegnasubramanian
Mone Zaidi
Kang Zhang
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Weiping Zou
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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 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
Computational BiologistPatrick Cahan
JCI ScholarsAnthony Bowen, Olurotimi Mesubi
Staff EditorsExecutive EditorSarah C. Jackson
Senior Science EditorCorinne Williams
Science EditorElyse Dankoski
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Editor at LargeUshma S. Neill
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JCI This Month ISSN 2324-7703 (print);ISSN 2325-4556 (online)
For the full JCI online: jci.me/129/9
This MonthSeptember 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 JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.
Featured Editor
Mariana Kaplan, MD, Associate Editor, is a Senior Investigator and Chief of the Systemic Autoimmunity Branch as well as Deputy Scientific Director of the Intramural Research Program at the National Institute of Arthritis and Musculo skeletal and Skin Diseases at the NIH. Her research focuses on characterizing the role of the innate immune system in the development of systemic rheumatic diseases such as systemic lupus erythematosus and rheumatoid arthritis. Dr. Kaplan also investigates mechanisms of vascular damage in autoimmunity. She is a member of the American Society for
Clinical Investigation and the Association of American Physicians.
Publication highlights
Liu Y, Lightfoot YL, Seto N, Carmona-Rivera C, Moore E, Goel R, O’Neil L, Mistry P, Hoffmann V, Mondal S, Premnath PN, Gribbons K, Dell’Orso S, Jiang K, Thompson PR, Sun HW, Coonrod SA, Kaplan MJ. Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7–dependent lupus. JCI Insight. 2018;3(23):124729.
Faridi MH, Khan SQ, Zhao W, Lee HW, Altintas MM, Zhang K, Kumar V, Armstrong AR, Carmona-Rivera C, Dorschner JM, Schnaith AM, Li X, Ghodke-Puranik Y, Moore E, Purmalek M, Irizarry-Caro J, Zhang T, Day R, Stoub D, Hoffmann V, Khaliqdina SJ, Bhargava P, Santander AM, Torroella-Kouri M, Issac B, Cimbaluk DJ, Zloza A, Prabhakar R, Deep S, Jolly M, Koh KH, Reichner JS, Bradshaw EM, Chen J, Moita LF, Yuen PS, Li Tsai W, Singh B, Reiser J, Nath SK, Niewold TB, Vazquez-Padron RI, Kaplan MJ, Gupta V. CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. J Clin Invest. 2017;127(4):1271–1283.
Carmona-Rivera C, Carlucci PM, Moore E, Lingampalli N, Uchtenhagen H, James E, Liu Y, Bicker KL, Wahamaa H, Hoffmann V, Catrina AI, Thompson P, Buckner JH, Robinson WH, Fox DA, Kaplan MJ. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol. 2017;2(10):eaag3358.
Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146–153.
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 92
research
Editor’s picks
on the jci cover
Tumors express EPHA2 and PTGS2 to promote an immunosuppressive milieuImmunotherapies harness the cytotoxic functions of CD8+ T cells to exert a robust antitumor response, but inadequate T cell infiltration within the tumor microenvironment can limit clinical efficacy. Nune Markosyan, Jinyang Li, and colleagues report that expression of the ephrin receptor EPHA2 inversely correlates with T cell infiltration in tumors derived from pancreatic ductal adenocarci-noma (PDA) patients. In mouse models of PDA, ablating Epha2 increased T cell infiltration and enhanced response to checkpoint immunotherapy, confirming EPHA2’s role in immunosuppression. This work further reveals that EPHA2 regulates the expression of downstream PTGS2 (encoding cyclooxygenase-2). PTGS2 upregulation correlated with poor T cell infiltration and worse survival outcomes in PDA patients. In mice, both Ptgs2 ablation and PTGS2 inhibition sensitized tumors to immunotherapy. Jose Conejo-Garcia’s accompanying Commentary calls for further investigation of EPHA2 and PTGS2 pathway inhibitors in combination with immunotherapy to address therapy-resis-tant disease in tumors with poor T cell infiltration. The cover image illustrates the dichotomy between immunologically “hot” and “cold” tumors as a yin and yang, with prominent infiltration by T cells (red fish) or myeloid cells (blue fish). In cold tumors, cancer cells (lily pads) express EPHA2 and PTGS2 (flowers), tipping the balance toward a noninflamed phenotype. The abundance and activity of infiltrating T cells predict response to immunotherapy. Image credit: Yuhang Ouyang.
Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)Nune Markosyan, Jinyang Li, Yu H. Sun, Lee P. Richman, Jeffrey H. Lin, Fangxue Yan, Liz Quinones, Yogev Sela, Taiji Yamazoe, Naomi Gordon, John W. Tobias, Katelyn T. Byrne, Andrew J. Rech, Garret A. FitzGerald, Ben Z. Stanger (ASCI), and Robert H. Vonderheide (ASCI) http://jci.me/127755
Related CommentaryBreaking barriers for T cells by targeting the EPHA2/TGF-β/COX-2 axis in pancreatic cancerJose R. Conejo-Garcia http://jci.me/130316
oncology
LEAP2 levels fluctuate during nutrient imbalance and weight lossmetabolism
Ghrelin is a hunger-stimulating hormone that increases during fasting and declines during obesity. Ghrelin signals through its receptor, GHSR, to stimulate food intake, regulate adiposity, and raise blood glucose. Bharath Mani and colleagues investi-gated the role of the recently identified endogenous GHSR inhibitor LEAP2 in multiple metabolic states in mice and humans. In mice, LEAP2 increased during obesity and oral glucose administration and decreased following fasting or weight loss. Findings were similar in humans, where LEAP2 levels positively correlated with plasma glucose and body mass, increased upon food intake in individuals with obesity, and decreased following gastric bypass surgery. In the accompanying Commentary, Zane Andrews details the questions raised by this new model in which a balance between LEAP2 and ghrelin coordinates GHSR signaling in response to changes in body mass and energy homeostasis.
LEAP2 changes with body mass and food intake in humans and miceBharath K. Mani, Nancy Puzziferri, Zhenyan He, Juan A. Rodriguez, Sherri Osborne-Lawrence, Nathan P. Metzger, Navpreet Chhina, Bruce Gaylinn, Michael O. Thorner, E. Louise Thomas, Jimmy D. Bell, Kevin W. Williams, Anthony P. Goldstone, and Jeffrey M. Zigman (ASCI) http://jci.me/125332
Related CommentaryThe next big LEAP2 understanding ghrelin functionZane B. Andrews http://jci.me/131023
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 9 3
JCI | Research: Editor’s picks
Cholinergic vagal neurons are vulnerable to oxidative stress–induced α-synuclein pathology
neuroscience
metabolism
GIPR/Rap1 signaling links overnutrition to hypothalamic leptin insensitivity
Parkinson’s disease is classically associated with α-synuclein pathology and dopaminergic neuron degeneration. Increasing evidence, however, points to additional populations of neurons as key targets of α-synuclein, including the acetylcholine-producing neurons of the dorsal motor nucleus of the vagus nerve (DMnX) in the brain stem. Ruth Musgrove and colleagues now demonstrate that murine DMnX neurons are highly susceptible to oxidative stress caused by the herbicide paraquat. Targeted overexpression of α-synuclein within DMnX neurons also induced oxidative stress that was enhanced by concomitant paraquat adminis-tration. Severe oxidative stress, as seen under this combined treatment protocol, exacerbated α-synuclein aggregation, increased neuron-to-neuron α-synuclein transfer, promoted α-synuclein spreading throughout the mouse brain, and enhanced the degeneration in DMnX neurons (see the associated image). In vitro observations support the concept that oxidative modifications could facilitate the spreading of pathological α-synuclein. Kelvin Luk’s accompanying Commentary highlights these insights into Parkinson’s disease progression, which underscore the contribution of oxidative stress to disease pathogenesis.
Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transferRuth E. Musgrove, Michael Helwig, Eun-Jin Bae, Helia Aboutalebi, Seung-Jae Lee, Ayse Ulusoy, and Donato A. Di Monte http://jci.me/127330
Related CommentaryOxidative stress and α-synuclein conspire in vulnerable neurons to promote Parkinson’s disease progressionKelvin C. Luk http://jci.me/130351
Food intake increases levels of leptin, a satiety signal that helps control energy homeostasis and body weight. Chronic overnutrition and obesity are associated with leptin resistance in multiple systems, including the CNS. A team led by Makoto Fukuda demonstrated that the receptor for the gut-derived hormone GIP (GIPR) is a key controller of leptin sensitivity in the hypothalamus, the brain’s hub for regulating appetite and energy stores. Blocking GIPR systemically reduced weight gain and food intake in obese mice in a leptin-dependent manner. Conversely, enhancing neural GIP/GIPR signaling prevented leptin-induced reductions in food intake and body weight, an effect mediated by activation of the GTPase Rap1. In the accompanying Commentary, Jessica Yue and Tony Lam outline the evidence for this gut-brain connection’s contribution to leptin resistance in diet-induced obesity.
Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutritionKentaro Kaneko, Yukiko Fu, Hsiao-Yun Lin, Elizabeth L. Cordonier, Qianxing Mo, Yong Gao, Ting Yao, Jacqueline Naylor, Victor Howard, Kenji Saito, Pingwen Xu, Siyu S. Chen, Miao-Hsueh Chen, Yong Xu, Kevin W. Williams, Peter Ravn, and Makoto Fukuda http://jci.me/126107
Related CommentaryAntiobesogenic effects of central GIPR antagonismJessica T.Y. Yue and Tony K.T. Lam http://jci.me/130755
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JCI | Research: Editor’s picks
PHD2 silencing drives HIF2α-dependent inflammation and Treg dysfunction
PAHSA supplementation protects β cells in autoimmune diabetic miceIn type 1 diabetes (T1D), insulin-secreting β cells are destroyed by proinflammatory immune cells and cytokines that infiltrate the pancreas. As methods to predict T1D risk improve, identifying approaches that promote immune tolerance to β cells may help prevent β cell destruction in vulnerable individuals. PAHSAs are a recently identified class of lipids that have antiinflam-matory and antidiabetic effects, and Ismail Syed and colleagues now show that they improve T1D pathology in NOD mice and have direct protective effects in human islets. Daily oral PAHSA supplementation delayed or prevented T1D onset, decreased inflammatory T cell infiltration to the pancreas, and improved glucose tolerance and glucose-stimulated insulin secretion in NOD mice. PAHSAs also increased β cell proliferation and islet volume and had direct protective effects linked to reductions in ER stress and MAPK signaling. In the accompanying Commentary, Abdel Rahim Hamad and colleagues weigh the evidence supporting PAHSA supplementation’s beneficial effects on β cells in the setting of autoimmune diabetes.
PAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic miceIsmail Syed, Maria F. Rubin de Celis, James F. Mohan, Pedro M. Moraes-Vieria, Archana Vijayakumar, Andrew T. Nelson, Dionicio Siegel, Alan Saghatelian, Diane Mathis, and Barbara B. Kahn (ASCI) http://jci.me/122445
Related CommentaryHybrid lipids, peptides, and lymphocytes: new era in type 1 diabetes researchAbdel Rahim A. Hamad, Mohanraj Sadasivam, and Hamid Rabb (ASCI) http://jci.me/130313
autoimmunity
HIFs are transcription factors that transduce changes in oxygen into physiological responses across all tissue and cell types. PHD enzymes directly sense oxygen levels and regulate HIF function. Atsushi Yamamoto, Joanna Hester, and colleagues used a new recombinant mouse model with drug-induced shRNA expression to explore PHD/HIF regulation in a time-controlled, reversible manner. Long-term systemic silencing of PHD2 in adult mice led to progressive multilineage leukocytosis/lymphadenopathy, inflammation in multiple organs, and development of antinuclear antibodies, suggestive of autoimmunity (see the associated image). The phenotype was seen when PHD2 silencing was restricted to cells of bone marrow origin, reverted when PHD2 expression was restored, and prevented by simultaneous silencing of HIF2α. Cells bearing Treg markers from these mice exhibited defective function and proinflamma-tory effects in vivo. Weiping Zou and Yatrik Shah discuss this previously unappreciated role for PHD2/HIF2α signaling in immune regulation in the accompanying Commentary.
Systemic silencing of Phd2 causes reversible immune regulatory dysfunctionAtsushi Yamamoto, Joanna Hester, Philip S. Macklin, Kento Kawai, Masateru Uchiyama, Daniel Biggs, Tammie Bishop, Katherine Bull, Xiaotong Cheng, Eleanor Cawthorne, Mathew L. Coleman, Tanya L. Crockford, Ben Davies, Lukas E. Dow, Rob Goldin, Kamil Kranc, Hiromi Kudo, Hannah Lawson, James McAuliffe, Kate Milward, Cheryl L. Scudamore, Elizabeth Soilleux, Fadi Issa, Peter J. Ratcliffe, and Chris W. Pugh http://jci.me/124099
Related CommentaryA PHD in immunosuppression: oxygen-sensing pathways regulate immunosuppressive TregsWeiping Zou and Yatrik M. Shah http://jci.me/130009
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JCI | Research: Editor’s picks
infectious disease
X-linked histone demethylase KDM6A may underlie sex differences in autoimmunity
Clostridioides difficile infection leaves its mark on the fecal metabolome
autoimmunity
Multiple sclerosis (MS) is diagnosed in more women than men, suggesting that differences in sex hormones or chromosomes may contribute to its pathology. Yuichiro Itoh and colleagues investigated whether sexually dimorphic expression of the X-linked histone demethylase KDM6A contributes to enhanced susceptibility to autoimmunity. Female humans and mice both expressed higher levels of KDM6A than male counterparts. Delet-ing Kdm6a in CD4+ T cells, the primary effectors of MS-like pathology, improved clinical scores and reduced spinal cord inflammation and axonal pathology in both sexes in a mouse model (see the associated image). Kdm6a deficiency also altered the transcriptome in CD4+ T cells, skewing toward Th1/Th2 activation and downregulating neuroinflammatory pathways. Gregory Wu’s accompanying Commentary outlines this mechanis-tic foundation for sex differences in MS incidence, supporting further investigation of KDM6A’s relevance in autoimmune disease pathology.
The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunityYuichiro Itoh, Lisa C. Golden, Noriko Itoh, Macy Akiyo Matsukawa, Emily Ren, Vincent Tse, Arthur P. Arnold, and Rhonda R. Voskuhl http://jci.me/126250
Related CommentaryX-tra X: an escape to autoimmunityGregory F. Wu http://jci.me/130312
Antibiotic use is a risk factor for intestinal infection with antibiotic-resistant Clostridioides difficile, suggesting that suppressing a healthy gut microbiome increases the organism’s pathogenic potential. Accurately diagnosing C. difficile infection (CDI) can be challenging due to the false-positive and false-negative results associated with clinically available assays. John Robinson and colleagues analyzed the fecal metabolomes of 186 hospitalized patients to characterize CDI-associated small-molecule profiles using an unbiased screening approach. Chemical signatures in clinical samples from CDI patients included products of bile acid metabolism and leucine fermentation that distinguished CDI patients from those with non-CDI diarrhea. In the accompanying Commentary, Casey Theriot and Joshua Fletcher give clinical context to this metab olomic model, suggesting that it may improve diagnostic accuracy and help identify new virulence-targeting therapeutic strategies.
Metabolomic networks connect host-microbiome processes to human Clostridioides difficile infectionsJohn I. Robinson, William H. Weir, Jan R. Crowley, Tiffany Hink, Kimberly A. Reske, Jennie H. Kwon, Carey-Ann D. Burnham, Erik R. Dubberke, Peter J. Mucha, and Jeffrey P. Henderson (ASCI) http://jci.me/126905
Related CommentaryHuman fecal metabolomic profiling could inform Clostridioides difficile infection diagnosis and treatmentCasey M. Theriot and Joshua R. Fletcher http://jci.me/130008
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JCI | Features
viewpoints
reviews
Confronting gender and racial bias in academic medicineIn the summer of 2018, a study by the National Academies of Science, Engineering, and Medicine (NASEM) revealed that over 50% of female faculty and staff in academic institutions had experienced some form of harassment, most frequently gender based. Women in academic medicine reported the highest incidence of sexual harassment in any field studied. NASEM’s report highlights just one challenge contributing to persistent underrepresentation of women scientists in positions of leadership. Two Viewpoints in this issue of the JCI discuss the barriers to women in academic medicine. Whitney Beeler, Lilia Cortina, and Reshma Jagsi discuss the overt and covert behaviors that create an environment that is biased against the success of women and gender minorities (see the associated image). Sherita Hill Golden describes the additional layers of racial bias affecting women of color that hinder efforts to achieve diverse leadership within academic communities. Both Viewpoints call for organizations to lead the way in supporting gender equality and prodiversity initiatives, and fostering environments that do not tolerate harassment and bias.
Harnessing the killer instincts of NK cells to fight cancerAlthough NK cells play a key role in cancer immunosurveillance, cancer cells have developed mechanisms to evade detection and cytotoxic attack. The immunosuppressive tumor microenvironment contains numerous signals that suppress NK cell function. In spite of this, NK cells are now known to participate in the efficacy of conventional cancer treatments such as radiation and chemo-therapy. Michele Ardolino and colleagues review the current understanding of NK cell activity and suppression in cancer and highlight the numerous strategies in development to mobilize these deadly sentinels against tumors. They describe adoptive cell transfer, checkpoint blockade, oncolytic virotherapy, and other approaches in preclinical and clinical development to galvanize NK cells’ natural cancer-fighting abilities.
Killers 2.0: NK cell therapies at the forefront of cancer controlJonathan J. Hodgins, Sarwat T. Khan, Maria M. Park, Rebecca C. Auer, and Michele Ardolino http://jci.me/129338
Putting the spotlight on innate immunity in tuberculosis vaccinationThe bacille Calmette-Guérin (BCG) vaccine against tuberculosis has been in use for nearly 100 years. It offers vaccinated infants and children over 50% protection against pulmonary disease but performs poorly in adolescents and adults. Improving our understanding of the immune mechanisms controlling tuberculosis infection in vaccinated individuals may be a critical step toward improving the efficacy of future vaccination strategies. Shabaana Khader and colleagues from the Bill and Melinda Gates Collaboration for TB Vaccine Discovery discuss evidence that a form of innate immune memory termed “trained immunity” contributes critically to the efficacy of the BCG vaccine. Their Review provides a framework for understanding how focusing on trained immunity may be the key to enhancing the protection provided by future tuberculosis vaccines.
Targeting innate immunity for tuberculosis vaccinationShabaana A. Khader, Maziar Divangahi, Willem Hanekom, Philip C. Hill, Markus Maeurer, Karen W. Makar, Katrin D. Mayer-Barber, Musa M. Mhlanga, Elisa Nemes, Larry S. Schlesinger, Reinout van Crevel, Ramakrishna Vankalayapati, Ramnik J. Xavier, and Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group http://jci.me/128877
The perils of intersectionality: racial and sexual harassment in medicineSherita Hill Golden (ASCI) http://jci.me/130900
Diving beneath the surface: addressing gender inequities among clinical investigatorsWhitney H. Beeler, Lilia M. Cortina, and Reshma Jagsi (ASCI) http://jci.me/130901
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Current research articles
autoimmunityPAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic mice p. 4Ismail Syed, Maria F. Rubin de Celis, James F. Mohan, Pedro M. Moraes-Vieira, Archana Vijayakumar, Andrew T. Nelson, Dionicio Siegel, Alan Saghatelian, Diane Mathis, and Barbara B. Kahn (ASCI) http://jci.me/122445
Systemic silencing of Phd2 causes reversible immune regulatory dysfunction p. 4Atsushi Yamamoto, Joanna Hester, Philip S. Macklin, Kento Kawai, Masateru Uchiyama, Daniel Biggs, Tammie Bishop, Katherine Bull, Xiaotong Cheng, Eleanor Cawthorne, Mathew L. Coleman, Tanya L. Crockford, Ben Davies, Lukas E. Dow, Rob Goldin, Kamil Kranc, Hiromi Kudo, Hannah Lawson, James McAuliffe, Kate Milward, Cheryl L. Scudamore, Elizabeth Soilleux, Fadi Issa, Peter J. Ratcliffe, and Chris W. Pugh http://jci.me/124099
The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity p. 5Yuichiro Itoh, Lisa C. Golden, Noriko Itoh, Macy Akiyo Matsukawa, Emily Ren, Vincent Tse, Arthur P. Arnold, and Rhonda R. Voskuhl http://jci.me/126250
dermatologyRecurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinomaShigeki Sekine, Tohru Kiyono, Eijitsu Ryo, Reiko Ogawa, Susumu Wakai, Hitoshi Ichikawa, Koyu Suzuki, Satoru Arai, Koji Tsuta, Mitsuaki Ishida, Yuko Sasajima, Naoki Goshima, Naoya Yamazaki, and Taisuke Mori http://jci.me/126185
endocrinologyTDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in isletsKunihiko Araki, Amane Araki, Daiyu Honda, Takako Izumoto, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yohei Iguchi, Akitoshi Hara, Kazuhiro Ikumi, Kaori Kawai, Shinsuke Ishigaki, Yoko Nakamichi, Shin Tsunekawa, Yusuke Seino, Akiko Yamamoto, Yasunori Takayama, Shihomi Hidaka, Makoto Tominaga, Mica Ohara-Imaizumi, Atsushi Suzuki, Hiroshi Ishiguro, Atsushi Enomoto, Mari Yoshida, Hiroshi Arima, Shin-ichi Muramatsu, Gen Sobue, and Masahisa Katsuno http://jci.me/124481
β Cell–intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretionLuiz F. Barella, Mario Rossi, Lu Zhu, Yinghong Cui, Fang C. Mei, Xiaodong Cheng, Wei Chen, Vsevolod V. Gurevich, and Jürgen Wess http://jci.me/126309
gastroenterologyMicrobiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10–producing regulatory B cellsYoshiyuki Mishima, Akihiko Oka, Bo Liu, Jeremy W. Herzog, Chang Soo Eun, Ting-Jia Fan, Emily Bulik-Sullivan, Ian M. Carroll, Jonathan J. Hansen, Liang Chen, Justin E. Wilson, Nancy C. Fisher, Jenny P.Y. Ting, Tomonori Nochi, Angela Wahl, J. Victor Garcia, Christopher L. Karp, and R. Balfour Sartor http://jci.me/93820
Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammationJia He, Yinjing Song, Gaopeng Li, Peng Xiao, Yang Liu, Yue Xue, Qian Cao, Xintao Tu, Ting Pan, Zhinong Jiang, Xuetao Cao, Lihua Lai, and Qingqing Wang http://jci.me/123374
Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease modelDavid Meriwether, Dawoud Sulaiman, Carmen Volpe, Anna Dorfman, Victor Grijalva, Nasrin Dorreh, R. Sergio Solorzano-Vargas, Jifang Wang, Ellen O’Connor, Jeremy Papesh, Muriel Larauche, Hannah Trost, Mayakonda N. Palgunachari, G.M. Anantharamaiah, Harvey R. Herschman, Martin G. Martin, Alan M. Fogelman, and Srinivasa T. Reddy http://jci.me/123700
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Current research articles
hematologyTGF-β signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond syndromeCailin E. Joyce, Assieh Saadatpour, Melisa Ruiz-Gutierrez, Ozge Vargel Bolukbasi, Lan Jiang, Dolly D. Thomas, Sarah Young, Inga Hofmann, Colin A. Sieff, Kasiani C. Myers, Jennifer Whangbo, Towia A. Libermann, Chad Nusbaum, Guo-Cheng Yuan, Akiko Shimamura, and Carl D. Novina http://jci.me/125375
immunologyBystander responses impact accurate detection of murine and human antigen-specific CD8+ T cellsMatthew D. Martin, Isaac J. Jensen, Andrew S. Ishizuka, Mitchell Lefebvre, Qiang Shan, Hai-Hui Xue, John T. Harty, Robert A. Seder, and Vladimir P. Badovinac http://jci.me/124443
Chronic stimulation drives human NK cell dysfunction and epigenetic reprogramingAimee Merino, Bin Zhang, Philip Dougherty, Xianghua Luo, Jinhua Wang, Bruce R. Blazar, Jeffrey S. Miller, and Frank Cichocki http://jci.me/125916
CD161 contributes to prenatal immune suppression of IFN-γ–producing PLZF+ T cellsJoanna Halkias, Elze Rackaityte, Sara L. Hillman, Dvir Aran, Ventura F. Mendoza, Lucy R. Marshall, Tippi C. MacKenzie, and Trevor D. Burt http://jci.me/125957
Allergen presensitization drives an eosinophil-dependent arrest in lung-specific helminth developmentPedro H. Gazzinelli-Guimaraes, Rafael de Queiroz Prado, Alessandra Ricciardi, Sandra Bonne-Année, Joshua Sciurba, Erik P. Karmele, Ricardo T. Fujiwara, and Thomas B. Nutman (ASCI) http://jci.me/127963
infectious diseaseIFN-I response timing relative to virus replication determines MERS coronavirus infection outcomesRudragouda Channappanavar, Anthony R. Fehr, Jian Zheng, Christine Wohlford-Lenane, Juan E. Abrahante, Matthias Mack, Ramakrishna Sompallae, Paul B. McCray Jr., David K. Meyerholz, and Stanley Perlman http://jci.me/126363
Metabolomic networks connect host-microbiome processes to human Clostridioides difficile infections p. 5John I. Robinson, William H. Weir, Jan R. Crowley, Tiffany Hink, Kimberly A. Reske, Jennie H. Kwon, Carey-Ann D. Burnham, Erik R. Dubberke, Peter J. Mucha, and Jeffrey P. Henderson (ASCI) http://jci.me/126905
Human VP8* mAbs neutralize rotavirus selectively in human intestinal epithelial cellsNingguo Feng, Liya Hu, Siyuan Ding, Mrinmoy Sanyal, Boyang Zhao, Banumathi Sankaran, Sasirekha Ramani, Monica McNeal, Linda L. Yasukawa, Yanhua Song, B.V. Venkataram Prasad, and Harry B. Greenberg (ASCI) http://jci.me/128382
inflammationDectin-2–induced CCL2 production in tissue-resident macrophages ignites cardiac arteritisChie Miyabe, Yoshishige Miyabe, Laura Bricio-Moreno, Jeffrey Lian, Rod A. Rahimi, Noriko N. Miura, Naohito Ohno, Yoichiro Iwakura, Tamihiro Kawakami, and Andrew D. Luster (ASCI) http://jci.me/123778
TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunityLi Xu, Yiming Li, Chenxuan Yang, Patricia Loughran, Hong Liao, Rosemary Hoffman, Timothy R. Billiar, and Meihong Deng http://jci.me/127542
metabolismLEAP2 changes with body mass and food intake in humans and mice p. 2Bharath K. Mani, Nancy Puzziferri, Zhenyan He, Juan A. Rodriguez, Sherri Osborne-Lawrence, Nathan P. Metzger, Navpreet Chhina, Bruce Gaylinn, Michael O. Thorner, E. Louise Thomas, Jimmy D. Bell, Kevin W. Williams, Anthony P. Goldstone, and Jeffrey M. Zigman (ASCI) http://jci.me/125332
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Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition p. 3Kentaro Kaneko, Yukiko Fu, Hsiao-Yun Lin, Elizabeth L. Cordonier, Qianxing Mo, Yong Gao, Ting Yao, Jacqueline Naylor, Victor Howard, Kenji Saito, Pingwen Xu, Siyu S. Chen, Miao-Hsueh Chen, Yong Xu, Kevin W. Williams, Peter Ravn, and Makoto Fukuda http://jci.me/126107
nephrologyThe archaeal Dps nanocage targets kidney proximal tubules via glomerular filtrationMasaki Uchida, Bernhard Maier, Hitesh Kumar Waghwani, Ekaterina Selivanovitch, S. Louise Pay, John Avera, EJun Yun, Ruben M. Sandoval, Bruce A. Molitoris, Amy Zollman, Trevor Douglas, and Takashi Hato http://jci.me/127511
neuroscienceMultiple stimulation parameters influence efficacy of deep brain stimulation in parkinsonian miceJonathan S. Schor and Alexandra B. Nelson http://jci.me/122390
TMEM25 modulates neuronal excitability and NMDA receptor subunit NR2B degradationHaiqing Zhang, Xin Tian, Xi Lu, Demei Xu, Yi Guo, Zhifang Dong, Yun Li, Yuanlin Ma, Chengzhi Chen, Yong Yang, Min Yang, Yi Yang, Feng Liu, Ruijiao Zhou, Miaoqing He, Fei Xiao, and Xuefeng Wang http://jci.me/122599
Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer p. 3Ruth E. Musgrove, Michael Helwig, Eun-Jin Bae, Helia Aboutalebi, Seung-Jae Lee, Ayse Ulusoy, and Donato A. Di Monte http://jci.me/127330
Neuronal FcγRI mediates acute and chronic joint painLi Wang, Xiaohua Jiang, Qin Zheng, Sang-Min Jeon, Tiane Chen, Yan Liu, Heather Kulaga, Randall Reed, Xinzhong Dong, Michael J. Caterina, and Lintao Qu http://jci.me/128010
oncologyTumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2) p. 2Nune Markosyan, Jinyang Li, Yu H. Sun, Lee P. Richman, Jeffrey H. Lin, Fangxue Yan, Liz Quinones, Yogev Sela, Taiji Yamazoe, Naomi Gordon, John W. Tobias, Katelyn T. Byrne, Andrew J. Rech, Garret A. FitzGerald, Ben Z. Stanger (ASCI), and Robert H. Vonderheide (ASCI) http://jci.me/127755
N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancerAdeline Berger, Nicholas J. Brady, Rohan Bareja, Brian Robinson, Vincenza Conteduca, Michael A. Augello, Loredana Puca, Adnan Ahmed, Etienne Dardenne, Xiaodong Lu, Inah Hwang, Alyssa M. Bagadion, Andrea Sboner, Olivier Elemento, Jihye Paik, Jindan Yu, Christopher E. Barbieri, Noah Dephoure, Himisha Beltran, and David S. Rickman http://jci.me/127961
Antibodies targeting sialyl Lewis A mediate tumor clearance through distinct effector pathwaysPolina Weitzenfeld, Stylianos Bournazos, and Jeffrey V. Ravetch (ASCI) http://jci.me/128437
vascular biologyRASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular developmentDi Chen, Joyce M. Teng, Paula E. North, Philip E. Lapinski, and Philip D. King http://jci.me/124917
Roles of HIFs and VEGF in angiogenesis in the retina and brainAmir Rattner, John Williams, and Jeremy Nathans http://jci.me/126655
Flip issue to read JCI Insight content.
jci.org/this-month
Sorafenib-mediated changes in immune cell subsets of HCC patients 11
Prohibitin linked to Wilms’ tumor severity and treatment resistance 12
Extraintestinal microbiota enhances allograft rejection 13
Gut-associated lymphoid tissue depletes self-reactive B cells 13
JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
September 2019
Mutant lysyl oxidase in aortic dilation p. 11
This Month
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 1 917
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
Timothy 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
Michael G. Kaplitt
Thomas W.H. Kay
Barbara I. Kazmierczak
Hans-Peter Kiem
William Y. Kim
David G. Kirsch
Claire E. Lewis
Mathias Lichterfeld
André Lieber
Michail S. Lionakis
Carey N. Lumeng
Ivan Maillard
Ziad Mallat
Peter Mannon
Franck Mauvais-Jarvis
Dermot P.B. McGovern
Borna Mehrad
Ingo K. Mellinghoff
David K. Meyerholz
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
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
Deborah J. Veis
Charles P. Venditti
Joseph M. Vinetz
Sing Sing Way
Bernd Wollnik
Minna Woo
Prescott G. Woodruff
Lori M. Zeltser
Yutong Zhao
Binhua P. Zhou
JCI Insight Consulting Editors
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For JCI InsightEditorKathleen CollinsDeputy EditorsAndrew Lieberman, Donna Martin, Pavan ReddyAssociate EditorsSharlene M. Day, David A. Fox, Santhi Ganesh, John Y. Kao, Celina G. Kleer, Carey Lumeng, Lona Mody, Bethany B. Moore, Alexey Nesvizhskii, Akinlolu Ojo, Marina Pasca di Magliano, Darleen Sandoval, Andrew Tai, Weiping ZouExecutive EditorSarah C. JacksonSenior Science EditorCorinne Williams
ASCI StaffExecutive DirectorJohn B. HawleyManaging DirectorKaren D. GuthAssociate DirectorMaya HoptmanAssociate Director, TechnologyShawn PyleProduction EditorsCatherine Ahmann, Ken Beauchamp, Molly Jean, Lara L. McCarronProduction AssistantKatherine A. BullenScientific IllustratorBruce WordenCopy EditorsClare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, Chet ProvodaAssociate Copy EditorMegan ReilleyAssociate Editor, Copy and ProductionRachel BullenEditorial AssistantCady VishniacPublications CoordinatorMegan JenkinsSystem Administrator and DeveloperBryan EnglishSoftware DevelopersAustin Brewer, Jose L. JardonScience Communications SpecialistNeha AggarwalAccounts ManagerPaula KremidasAdministrative AssistantTheresa KaiserFigures CoordinatorKeith Kalinowski
For JCI Insight online: jci.me/insight/4/15jci.me/insight/4/16
From the Editor
This MonthSeptember 2019 A new editor for JCI Insight
This issue marks the first transition of the Editorial Board of JCI Insight from its founding site at Duke University to a new home at the University of Michigan. Launched by a team led by Howard Rockman less than four years ago, the ASCI’s newest journal has succeeded in providing an important forum for high-quality research papers.
In addition to submitting directly to JCI Insight, authors can submit manu-scripts reviewed externally elsewhere, accompanied by reviewer comments, for consideration. In many cases, the journal will continue to invite manuscripts reviewed and rejected by the JCI for potential publication in JCI Insight. It’s clear that authors have welcomed the opportunity to facilitate rapid reporting of high-quality, high-impact research.
JCI Insight’s success comes at an opportune time, when emerging technologies will enable greater insights into disease pathogenesis using clinical samples. Our board aims to provide a forum for new technologies as well as patient-based studies that employ them to uncover insights into disease pathogenesis, biomarkers, and treatment. ASCI members are an important source of this research, and we welcome their interest and engagement. To encourage phy-sician-scientist training, we plan to develop a JCI Insight Scholars Program for physician-scientist trainees at the University of Michigan, analogous to a suc-cessful program developed at Johns Hopkins University by the JCI Board.
Most importantly, as the new Editor in Chief, I will complete the maturation of JCI Insight by providing an expanded board with additional subject matter expertise to evaluate the rapidly growing number of direct manuscript sub-missions. I am delighted that our new editorial team provides broad scientific expertise as well as in-depth editorial experience. Each editor is committed to his/her role and is enthusiastic about bringing JCI Insight to the next level. Our vision is to report original impactful discoveries that uphold the high standards expected by ASCI members, authors, and the readership.
I am very excited about the challenge and responsibility to further enhance the status and impact of JCI Insight. I look forward to working with the JCI Insight Editorial Board members, the JCI Insight staff, and the ASCI organization.
Kathleen L. CollinsEditor in Chief, JCI Insight
To read Dr. Collins’s complete editorial, see http://jci.me/132119.
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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Editor’s picks
on the jci insight cover
Lysyl oxidase mutation promotes aortic dilation following hemodynamic stressThoracic aortic aneurysm and dissection (TAAD) has been linked to a variety of mutations that alter vascular extracellular matrix, smooth muscle function, and/or growth factor signaling. Heterozygous, missense mutations in lysyl oxidase (LOX), which promotes elastin crosslinking, are linked to TAAD; however, not all carriers develop disease. Vivian Lee, Carmen Halabi, and colleagues generated mice harboring a single copy of a TAAD-associated Lox allele (M292R) and found that animals developed aneurysmal disease only in conjunc-tion with hypertension, as the result of vessel wall thickening and alterations in aortic cell populations, including a decrease in smooth muscle cells and increased immune cell infiltration. The M292R mutation prevented LOX transit from the ER to the Golgi, resulting intracellular retention. These results reveal pathways by which mutant LOX promotes TAAD in the presence of hemodynamic stress. The cover image shows immune cell infiltration (CD68, green) and elastin staining (red) in a descending aorta of a WT mouse following treatment with angiotensin II. Nuclei stained blue with DAPI.
Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stressVivian S. Lee, Carmen M. Halabi, Thomas J. Broekelmann, Philip C. Trackman, Nathan O. Stitziel, and Robert P. Mecham http://jci.me/127748
Immune cell subsets linked to sorafenib response in HCC patients
cell biology
hepatology
Sorafenib improves survival in a subset of patients with hepatocellular carcinoma (HCC) but is associated with several toxicities that limit long-term use. Suresh Kalathil and colleagues collected blood samples from a small cohort of HCC patients before and at two time points after sorafenib treatment to evaluate changes in immune cell populations and duration of these changes. An increase in IFN-γ–producing CD8+Ki67+ T cells associated with treatment response and improved
survival. Patients with a high level of CD4+ effector T cells compared with Tregs prior to treatment also had increased overall survival in response to sorafenib. Moreover, sorafenib was shown to hinder immunosuppressive cell subsets, including ERK+flt-3+ Tregs and myeloid-derived suppressor cells, and higher baseline levels of flt-3+pERK+ MDSCs associated with improved survival. These results provide markers with the potential to improve identification of patients likely to benefit from
sorafenib treatment and evaluate treatment efficacy, thereby reducing exposure to toxic therapies and affecting treatment cost, quality of life, and patient survival.
Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapySuresh Gopi Kalathil, Alan Hutson, Joseph Barbi, Renuka Iyer, and Yasmin Thanavala http://jci.me/130116
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JCI Insight | Editor’s picks
12
cardiology
Modeling cardiac norepinephrine deficiency in Lewy body diseases
Prohibitin is a potential marker and therapeutic target for Wilms’ tumor
cell biology
Wilms’ tumor is the most common childhood kidney cancer, and patients with low-risk disease have a high cure rate. Unfortunately, therapeutic options are limited for patients with advanced, anaplastic, or relapsed disease, and identification of patients at risk of relapse is challenging. Michael Ortiz and colleagues compared urine proteomic profiles from patients with Wilms’ tumor, patients with non–Wilms’ tumor renal tumors, and controls and uncovered an association between elevated prohibitin in the urine and Wilms’ tumor relapse. Moreover, prohibitin expression in Wilms’ tumor biopsies correlated with disease stage (see the accompanying image). Prohibitin overexpression promoted Wilms’ tumor growth and survival by blocking mitochondrial apoptosis, thereby rendering the Wilms’ tumor cells resistant to chemotherapy
treatment. Cumulatively, these results identify prohibitin as a marker of disease severity and a potential target for Wilms’ and other relapsed or refractory tumors.
Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumorMichael V. Ortiz, Saima Ahmed, Melissa Burns, Anton G. Henssen, Travis J. Hollmann, Ian MacArthur, Shehana Gunasekera, Lyvia Gaewsky, Gary Bradwin, Jeremy Ryan, Anthony Letai, Ying He, Arlene Naranjo, Yueh-Yun Chi, Michael LaQuaglia, Todd Heaton, Paolo Cifani, Jeffrey S. Dome, Samantha Gadd, Elizabeth Perlman, Elizabeth Mullen, Hanno Steen, and Alex Kentsis (ASCI) http://jci.me/127098
Lewy body diseases are a family of neurodegenera-tive disorders that often present with parkinsonism due to depletion of the catecholamine dopamine in the brain. In addition, deficiency of the closely related catecholamine norepinephrine (NE) in the heart in these conditions is associated with several nonmotor manifestations. The basis of NE loss has not been fully explored. David Goldstein and colleagues developed a computational model describing determinants of NE stores in cardiac
sympathetic nerves and tested the model in a cohort of patients with Parkinson disease (PD). Myocardial NE content was decreased by 99% in patients with PD compared with controls. The model revealed specific abnormalities of catecholamine biosynthesis, vesicular storage, and neuronal uptake as denervation-independent bases for the profound cardiac noradrenergic lesion. In Lewy body diseases, a subset of cardiac sympathetic nerves are dysfunctional but exhibit a “sick-but-not-dead”
phenotype, suggesting that treatment to rescue or preserve the neurons may be possible.
Computational modeling reveals multiple abnormalities of myocardial noradrenergic function in Lewy body diseasesDavid S. Goldstein (ASCI), Mark J. Pekker, Graeme Eisenhofer, and Yehonatan Sharabi http://jci.me/130441
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JCI Insight | Editor’s picks
Gut-associated lymphoid tissue keeps self-reactive B cells at bayGut-associated lymphoid tissue (GALT) is an important site for immune homeostasis and discrimination between self- and nonself-antigens. B cells are critical to the development of immune tolerance; however, it is not clear how GALT B cells are educated. Ashima Shukla, Cindi Chen, and colleagues developed a mouse model in which duck egg lysozyme (DEL) is expressed in gut epithelial cells in the presence of HEL-reactive B cells. Self-reactive B cells were transiently activated and rapidly depleted in GALT in response to self-antigen. Ectopic expression of survival factor BCL2 prevented self-reactive B cell death, resulting in autoantibody production and gut inflammation (see the accompanying image). Moreover, TGF-β signaling in self-reactive B cells was critical for tolerance, indicating that this pathway is a critical checkpoint for maintaining immune tolerance in the gut.
Self-reactive B cells in the GALT are actively curtailed to prevent gut inflammationAshima Shukla, Cindi Chen, Julia Jellusova, Charlotte R. Leung, Elaine Kao, Numana Bhat, Wai W. Lin, John R. Apgar, and Robert C. Rickert http://jci.me/130621
Skin microbiota influences allograft survivalOrgans, such as the heart and kidney, from sterile body sites have a longer half-life after transplantation compared with organs, such as the lung, that are colonized with commensal bacteria. Allograft rejection is delayed in antibiotic-treated and germ-free animals; however, the role of different microbiota niches in allograft rejection is not clear. Yuk Man Lei and colleagues determined that colonization of the skin of germ-free mice with Staphylococcus epidermidis, while preventing intestinal colonization with oral antibiotics, accelerates skin graft rejection. Moreover, both transplanta-tion of colonized donor skin and colonization of recipient skin prior to transplant enhanced graft rejection. Cutaneous S. epidermidis augmented alloreactive T cell function locally in the graft rather than at the priming phase in graft-draining lymph nodes. These results reveal that graft and extra-intesti-nal microbiota affect allograft outcome and suggest that targeting both recipient and donor microbiota prior to transplantation may improve outcomes.
Skin-restricted commensal colonization accelerates skin graft rejectionYuk Man Lei, Martin Sepulveda, Luqiu Chen, Ying Wang, Isabella Pirozzolo, Betty Theriault, Anita S. Chong, Yasmine Belkaid, and Maria-Luisa Alegre (ASCI) http://jci.me/127569
Autoimmune disease–associated alterations of PP2A B55β limit T cell apoptosis
autoimmunity
immunology
Chronic immune activation is an autoimmune disease hallmark that is characterized by autoantibodies and activated T cells. T cell exhaustion profiles associate with less severe disease; however, factors that determine duration and magnitude of the immune response in autoimmune disease are poorly understood. Iris Madera-Salcedo and colleagues evaluated T cells from healthy donors and patients with a variety of autoimmune diseases for expression of PP2A B55β, which is linked to cytokine withdrawal–induced death (CWID) of activated T cells. PP2A B55β regulation was altered in T cells from patients with autoimmune disease, resulting in protection from CWID. Moreover, inflammation-driven hypermethylation of regulatory elements within the PP2A B55β–encoding locus was linked to defective
CCCTC-binding factor interaction at this site. These results indicate that epigenetic alteration of PP2A B55β may result in failure to remove activated T cells in autoimmunity, thereby exacerbating disease.
PPP2R2B hypermethylation causes acquired apoptosis deficiency in systemic autoimmune diseasesIris K. Madera-Salcedo, Beatriz E. Sánchez-Hernández, Yevgeniya Svyryd, Marcela Esquivel-Velázquez, Noé Rodríguez-Rodríguez, María Isabel Trejo-Zambrano, H. Benjamín García-González, Gabriela Hernández-Molina, Osvaldo M. Mutchinick, Jorge Alcocer-Varela, Florencia Rosetti, and José C. Crispín http://jci.me/126457
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Current articlesRestoration of insulin receptor improves diabetic phenotype in T2DM miceYichen Wang, Heather Zhou, Oksana Palyha, and James Mu http://jci.me/124945
Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammationGesine M. Scharf, Katja Kilian, Julio Cordero, Yong Wang, Andrea Grund, Melanie Hofmann, Natali Froese, Xue Wang, Andreas Kispert, Ralf Kist, Simon J. Conway, Robert Geffers, Kai C. Wollert, Gergana Dobreva, Johann Bauersachs, and Joerg Heineke http://jci.me/126721
ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicitySiân R. Kitcher, Nerissa K. Kirkwood, Esra D. Camci, Patricia Wu, Robin M. Gibson, Van A. Redila, Julian A. Simon, Edwin W. Rubel, David W. Raible, Guy P. Richardson, and Corné J. Kros http://jci.me/126764
Podoplanin neutralization improves cardiac remodeling and function after myocardial infarctionMaria Cimini, Venkata Naga Srikanth Garikipati, Claudio de Lucia, Zhongjian Cheng, Chunlin Wang, May M. Truongcao, Anna Maria Lucchese, Rajika Roy, Cindy Benedict, David A. Goukassian, Walter J. Koch, and Raj Kishore http://jci.me/126967
Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumor p. 12Michael V. Ortiz, Saima Ahmed, Melissa Burns, Anton G. Henssen, Travis J. Hollmann, Ian MacArthur, Shehana Gunasekera, Lyvia Gaewsky, Gary Bradwin, Jeremy Ryan, Anthony Letai, Ying He, Arlene Naranjo, Yueh-Yun Chi, Michael LaQuaglia, Todd Heaton, Paolo Cifani, Jeffrey S. Dome, Samantha Gadd, Elizabeth Perlman, Elizabeth Mullen, Hanno Steen, and Alex Kentsis (ASCI) http://jci.me/127098
RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancerOghenekevwe M. Gbenedio, Caroline Bonnans, Delphine Grun, Chih-Yang Wang, Ace J. Hatch, Michelle R. Mahoney, David Barras, Mary Matli, Yi Miao, K. Christopher Garcia, Sabine Tejpar, Mauro Delorenzi, Alan P. Venook, Andrew B. Nixon, Robert S. Warren, Jeroen P. Roose, and Philippe Depeille http://jci.me/127552
Skin-restricted commensal colonization accelerates skin graft rejection p. 13Yuk Man Lei, Martin Sepulveda, Luqiu Chen, Ying Wang, Isabella Pirozzolo, Betty Theriault, Anita S. Chong, Yasmine Belkaid, and Maria-Luisa Alegre (ASCI) http://jci.me/127569
Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neuronsYingxiao Shi, Shu-Ting Hung, Gabriel Rocha, Shaoyu Lin, Gabriel R. Linares, Kim A. Staats, Carina Seah, Yaoming Wang, Michael Chickering, Jesse Lai, Tohru Sugawara, Abhay P. Sagare, Berislav V. Zlokovic, and Justin K. Ichida http://jci.me/127736
Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress p. 11Vivian S. Lee, Carmen M. Halabi, Thomas J. Broekelmann, Philip C. Trackman, Nathan O. Stitziel, and Robert P. Mecham http://jci.me/127748
Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesityMaria Plataki, LiChao Fan, Elizabeth Sanchez, Ziling Huang, Lisa K. Torres, Mitsuru Imamura, Yizhang Zhu, David E. Cohen, Suzanne M. Cloonan, and Augustine M.K. Choi (ASCI) http://jci.me/127823
An Hb-mediated circulating macrophage contributing to pulmonary vascular remodeling in sickle cell diseaseKatherine Redinus, Jin Hyen Baek, Ayla Yalamanoglu, Hye Kyung H. Shin, Radu Moldova, Julie W. Harral, Delaney Swindle, David Pak, Scott K. Ferguson, Rachelle Nuss, Kathryn Hassell, Eva Nozik-Grayck, Andre F. Palmer, Mehdi A. Fini, Vijaya Karoor, Kurt R. Stenmark, Paul W. Buehler, and David C. Irwin http://jci.me/127860
Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid diseaseTanya Sezin, Sripriya Murthy, Claudia Attah, Malte Seutter, Maike M. Holtsche, Christoph M. Hammers, Enno Schmidt, Fibi Meshrkey, Sadegh Mousavi, Detlef Zillikens, Miles A. Nunn, and Christian D. Sadik http://jci.me/128239
Niclosamide repurposed for the treatment of inflammatory airway diseaseInês Cabrita, Roberta Benedetto, Rainer Schreiber, and Karl Kunzelmann http://jci.me/128414
Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytomaAnna K. Scherger, Mona Al-Maarri, Hans C. Maurer, Markus Schick, Sabine Maurer, Rupert Öllinger, Irene Gonzalez-Menendez, Manuela Martella, Markus Thaler, Konstanze Pechloff, Katja Steiger, Sandrine Sander, Jürgen Ruland, Roland Rad, Leticia Quintanilla-Martinez, Frank T. Wunderlich, Stefan Rose-John, and Ulrich Keller http://jci.me/128435
Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinomaNilay Sethi, Osamu Kikuchi, James McFarland, Yanxi Zhang, Max Chung, Nicholas Kafker, Mirazul Islam, Benjamin Lampson, Abhishek Chakraborty, William G. Kaelin Jr., and Adam J. Bass (ASCI) http://jci.me/128439
Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heartHadi Khalil, Onur Kanisicak, Ronald J. Vagnozzi, Anne Katrine Johansen, Bryan D. Maliken, Vikram Prasad, Justin G. Boyer, Matthew J. Brody, Tobias Schips, Katja K. Kilian, Robert N. Correll, Kunito Kawasaki, Kazuhiro Nagata, and Jeffery D. Molkentin http://jci.me/128722
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 1 915
Current articles
Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseasesAlessia De Caneva, Fabiola Porro, Giulia Bortolussi, Riccardo Sola, Michela Lisjak, Adi Barzel, Mauro Giacca, Mark A. Kay, Kristian Vlahoviček, Lorena Zentilin, and Andrés F. Muro http://jci.me/128863
MondoA drives muscle lipid accumulation and insulin resistanceByungyong Ahn, Shibiao Wan, Natasha Jaiswal, Rick B. Vega, Donald E. Ayer, Paul M. Titchenell, Xianlin Han, Kyoung Jae Won, and Daniel P. Kelly (ASCI) http://jci.me/129119
SREBP-regulated adipocyte lipogenesis is dependent on substrate availability and redox modulation of mTORC1Clair Crewe, Yi Zhu, Vivian A. Paschoal, Nolwenn Joffin, Alexandra L. Ghaben, Ruth Gordillo, DaYoung Oh, Guosheng Liang, Jay D. Horton, and Philipp E. Scherer http://jci.me/129397
The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasisMathilde Mouchiroud, Étienne Camiré, Manal Aldow, Alexandre Caron, Éric Jubinville, Laurie Turcotte, Inès Kaci, Marie-Josée Beaulieu, Christian Roy, Sébastien M. Labbé, Thibault V. Varin, Yves Gélinas, Jennifer Lamothe, Jocelyn Trottier, Patricia L. Mitchell, Frédéric Guénard, William T. Festuccia, Philippe Joubert, Christopher F. Rose, Constantine J. Karvellas, Olivier Barbier, Mathieu C. Morissette, André Marette, and Mathieu Laplante http://jci.me/129492
High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhagePui Y. Lee, Nathan Nelson-Maney, Yuelong Huang, Anaïs Levescot, Qiang Wang, Kevin Wei, Pierre Cunin, Yi Li, James A. Lederer, Haoyang Zhuang, Shuhong Han, Edy Y. Kim, Westley H. Reeves, and Peter A. Nigrovic http://jci.me/129703
Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy p. 11Suresh Gopi Kalathil, Alan Hutson, Joseph Barbi, Renuka Iyer, and Yasmin Thanavala http://jci.me/130116
Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophyNatalie Hudson, Lucia Celkova, Alan Hopkins, Chris Greene, Federica Storti, Ema Ozaki, Erin Fahey, Sofia Theodoropoulou, Paul F. Kenna, Marian M. Humphries, Annie M. Curtis, Eleanor Demmons, Akeem Browne, Shervin Liddie, Matthew S. Lawrence, Christian Grimm, Mark T. Cahill, Pete Humphries, Sarah L. Doyle, and Matthew Campbell http://jci.me/130273
Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder functionYuan Hao, Lu Wang, Huan Chen, Warren G. Hill, Simon C. Robson, Mark L. Zeidel, and Weiqun Yu http://jci.me/122112
Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosisGang Liu, Marion A. Cooley, Andrew G. Jarnicki, Theo Borghuis, Prema M. Nair, Gavin Tjin, Alan C. Hsu, Tatt Jhong Haw, Michael Fricker, Celeste L. Harrison, Bernadette Jones, Nicole G. Hansbro, Peter A. Wark, Jay C. Horvat, W. Scott Argraves, Brian G. Oliver, Darryl A. Knight, Janette K. Burgess, and Philip M. Hansbro http://jci.me/124529
Nononcogenic restoration of the intestinal barrier by E. coli–delivered human EGFMira Yu, Juil Kim, Jung Hoon Ahn, and Yuseok Moon http://jci.me/125166
Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repairDong Im Cho, Hye-jin Kang, Ju Hee Jeon, Gwang Hyeon Eom, Hyang Hee Cho, Mi Ra Kim, Meeyoung Cho, Hye-yun Jeong, Hyen Chung Cho, Moon Hwa Hong, Yong Sook Kim, and Youngkeun Ahn http://jci.me/125437
Semaphorin 3E/PlexinD1 signaling is required for cardiac ventricular compactionReddemma Sandireddy, Dasan Mary Cibi, Priyanka Gupta, Anamika Singh, Nicole Tee, Akiyoshi Uemura, Jonathan A. Epstein, and Manvendra K. Singh http://jci.me/125908
PPP2R2B hypermethylation causes acquired apoptosis deficiency in systemic autoimmune diseases p. 13Iris K. Madera-Salcedo, Beatriz E. Sánchez-Hernández, Yevgeniya Svyryd, Marcela Esquivel-Velázquez, Noé Rodríguez-Rodríguez, María Isabel Trejo-Zambrano, H. Benjamín García-González, Gabriela Hernández-Molina, Osvaldo M. Mutchinick, Jorge Alcocer-Varela, Florencia Rosetti, and José C. Crispín http://jci.me/126457
NOX4 modulates macrophage phenotype and mitochondrial biogenesis in asbestosisChao He, Jennifer L. Larson-Casey, Dana Davis, Vidya Sagar Hanumanthu, Ana Leda F. Longhini, Victor J. Thannickal, Linlin Gu, and A. Brent Carter (ASCI) http://jci.me/126551
Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancerMeifang Yu, Nicholas D. Nguyen, Yanqing Huang, Daniel Lin, Tara N. Fujimoto, Jessica M. Molkentine, Amit Deorukhkar, Ya’an Kang, F. Anthony San Lucas, Conrad J. Fernandes, Eugene J. Koay, Sonal Gupta, Haoqiang Ying, Albert C. Koong, Joseph M. Herman, Jason B. Fleming, Anirban Maitra, and Cullen M. Taniguchi http://jci.me/126915
Mesenchymal stromal cells lower platelet activation and assist in platelet formation in vitroAvital Mendelson, Ana Nicolle Strat, Weili Bao, Peter Rosston, Georgia Fallon, Sophie Ohrn, Hui Zhong, Cheryl Lobo, Xiuli An, and Karina Yazdanbakhsh http://jci.me/126982
Deletion of PTPN22 improves effector and memory CD8+ T cell responses to tumorsRebecca J. Brownlie, David Wright, Rose Zamoyska, and Robert J. Salmond http://jci.me/127847
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 9 16
Flip issue to read JCI content.
Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acidsPanu K. Luukkonen, Auli Nick, Maarit Hölttä-Vuori, Christoph Thiele, Elina Isokuortti, Susanna Lallukka-Brück, You Zhou, Antti Hakkarainen, Nina Lundbom, Markku Peltonen, Marju Orho-Melander, Matej Orešič, Tuulia Hyötyläinen, Leanne Hodson, Elina Ikonen, and Hannele Yki-Järvinen http://jci.me/127902
Damage- and pathogen-associated molecular patterns play differential roles in late mortality after critical illnessJohn Eppensteiner, Jean Kwun, Uwe Scheuermann, Andrew Barbas, Alexander T. Limkakeng, Maggie Kuchibhatla, Eric A. Elster, Allan D. Kirk, and Jaewoo Lee http://jci.me/127925
Primary tumors induce neutrophil extracellular traps with targetable metastasis-promoting effectsRoni F. Rayes, Jack G. Mouhanna, Ioana Nicolau, France Bourdeau, Betty Giannias, Simon Rousseau, Daniela Quail, Logan Walsh, Veena Sangwan, Nicholas Bertos, Jonathan Cools-Lartigue, Lorenzo E. Ferri, and Jonathan D. Spicer http://jci.me/128008
Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cellsMarkus M. Xie, Shuyi Fang, Qiang Chen, Hong Liu, Jun Wan, and Alexander L. Dent http://jci.me/128076
Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload–associated maladaptationMona Malek Mohammadi, Aya Abouissa, Azizah Isyatul, Yinou Xie, Julio Cordero, Amir Shirvani, Anna Gigina, Maren Engelhardt, Felix A. Trogisch, Robert Geffers, Gergana Dobreva, Johann Bauersachs, and Joerg Heineke http://jci.me/128336
Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolutionAbdel Nasser Hosein, Huocong Huang, Zhaoning Wang, Kamalpreet Parmar, Wenting Du, Jonathan Huang, Anirban Maitra, Eric Olson, Udit Verma, and Rolf A. Brekken http://jci.me/129212
The long noncoding RNA MALAT1 predicts human islet isolation qualityWilson K.M. Wong, Guozhi Jiang, Anja E. Sørensen, Yi Vee Chew, Cody Lee-Maynard, David Liuwantara, Lindy Williams, Philip J. O’Connell, Louise T. Dalgaard, Ronald C. Ma, Wayne J. Hawthorne, Mugdha V. Joglekar, and Anandwardhan A. Hardikar http://jci.me/129299
A distinct glycerophospholipid metabolism signature of acute graft versus host disease with predictive valueYue Liu, Aijie Huang, Qi Chen, Xiaofei Chen, Yang Fei, Xiaoming Zhao, Weiping Zhang, Zhanying Hong, Zhenyu Zhu, Jianmin Yang, Yifeng Chai, Jianmin Wang, and Xiaoxia Hu http://jci.me/129494
Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathiesMarie-Laure Arotcarena, Mathieu Bourdenx, Nathalie Dutheil, Marie-Laure Thiolat, Evelyne Doudnikoff, Sandra Dovero, Andrea Ballabio, Pierre-Olivier Fernagut, Wassilios G. Meissner, Erwan Bezard, and Benjamin Dehay http://jci.me/129719
Glucagon lowers glycemia when β cells are activeMegan E. Capozzi, Jacob B. Wait, Jepchumba Koech, Andrew N. Gordon, Reilly W. Coch, Berit Svendsen, Brian Finan, David A. D’Alessio, and Jonathan E. Campbell http://jci.me/129954
A panel of 4 biomarkers for the early diagnosis and therapeutic efficacy of aGVHDXiaoping Li, Ting Chen, Qiangguo Gao, Wei Zhang, Yunshuo Xiao, Wen Zhu, Lingyu Zeng, Zhenyu Li, Shijie Yang, Rui Wang, Xiaoqi Wang, Yimei Feng, and Xi Zhang http://jci.me/130413
Computational modeling reveals multiple abnormalities of myocardial noradrenergic function in Lewy body diseases p. 12David S. Goldstein (ASCI), Mark J. Pekker, Graeme Eisenhofer, and Yehonatan Sharabi http://jci.me/130441
Self-reactive B cells in the GALT are actively curtailed to prevent gut inflammation p. 13Ashima Shukla, Cindi Chen, Julia Jellusova, Charlotte R. Leung, Elaine Kao, Numana Bhat, Wai W. Lin, John R. Apgar, and Robert C. Rickert http://jci.me/130621
Antisense oligonucleotides extend survival of prion-infected miceGregory J. Raymond, Hien Tran Zhao, Brent Race, Lynne D. Raymond, Katie Williams, Eric E. Swayze, Samantha Graffam, Jason Le, Tyler Caron, Jacquelyn Stathopoulos, Rhonda O’Keefe, Lori L. Lubke, Andrew G. Reidenbach, Allison Kraus, Stuart L. Schreiber, Curt Mazur, Deborah E. Cabin, Jeffrey B. Carroll, Eric Vallabh Minikel, Holly Kordasiewicz, Byron Caughey, and Sonia M. Vallabh http://jci.me/131175
reviewNecroptosis: a crucial pathogenic mediator of human diseaseMary E. Choi, David R. Price, Stefan W. Ryter, and Augustine M.K. Choi (ASCI) http://jci.me/128834
editorialCome sail awayHoward A. Rockman http://jci.me/131371