Ankyrin-B mutation impairs metabolism

A summary of this month’s Journal of Clinical Investigation

Also in this issue: Lymphatic vessel valve development 7 Cardiospheres polarize macrophages 8 Epigenetic regulation in liposarcoma 8 Alefacept protects β cells 9

Ankyrin-B mutation impairs metabolism p. 6

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Editor Howard A. Rockman Deputy Editors Garnett Kelsoe, Bryan L. Roth Associate Editors Soman N. Abraham, Vann Bennett, Gerard C. Blobe, Kathleen M. Caron, Marc G. Caron, John P. Chute, Thomas M. Coffman, Anna Mae Diehl, Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Cam Patterson, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Yiping Yang Clinical Medicine Associate Editors Michael A. Morse, Andrew J. Muir, Scott M. Palmer, Mark A. Stacy Asia Editor David M. Virshup Chair, Executive Council Robert J. Lefkowitz Biostatisticians Cynthia Coffman, Barry Moser, Maren Olsen Bioethicist Arthur L. Caplan Senior Science Editor Sarah C. Jackson Science Editor Jillian Hurst Assistant Science Editor Corinne Williams

Featured Editor

The JCI’s Editorial Board is composed of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the board meets weekly to discuss the manuscripts undergoing review.

Jeffrey C. Rathmell, Ph.D., Associate Editor, is an Associate Professor of Pharmacology and Cancer Biology and of Immunology at Duke University, and is also a member of the Duke Molecular Physiology Institute. His research focuses on mechanisms of metabolic regulation in the immune system and metabolism of lymphocytes in immunity and in leukemia. In addition to defining pathways that drive cancer metabolism and links between metabolism and cell death pathways, he has shown that T cell metabolism is closely tied to differentiation. In particular, effector lineage T cells utilize a metabolic program that resembles that of cancer cells, while suppressive regulatory T cells are metabolically distinct. The Rathmell lab now uses lymphocyte activation as a model for cancer metabolism and is exploring targeting lymphocyte metabolism to modify T cell differentiation in inflammatory diseases. Starting this fall, Dr. Rathmell will relocate to Vanderbilt University as a member of the Pathology, Microbiology, and Immunology Department, where he will direct the Vanderbilt Center for Immunobiology. Publication highlights Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M, Ilkayeva O, Winter PS, Liu X, Priyadharshini B, Slawinska ME, Haeberli L, Huck C, Turka LA, Wood KC, Hale LP, Smith PA, Schneider MA, MacIver NJ, Locasale JW, Newgard CB, Shinohara ML, Rathmell JC. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest. 2015;125(1):194–207. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, Anderson SM, Abel ED, Chen BJ, Hale LP, Rathmell JC. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014;20(1):61–72. Coloff JL, Macintyre AN, Nichols AG, Liu T, Gallo CA, Plas DR, Rathmell JC. Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition. Cancer Res. 2011;71(15):5204–5213.

Editor at Large Ushma S. Neill ISSN 2324-7703 (print) ISSN 2325-4556 (online) The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

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Research articles in the current issue of the JCI Aging Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity Muscle type transformation

Shihyin Tsai, Joanna M. Sitzmann, Somasish G. Dastidar, Ariana A. Rodriguez, Stephanie L. Vu, Circe E. McDonald, Emmeline C. Academia, Monique N. O’Leary, Travis D. Ashe, Albert R. La Spada, and Brian K. Kennedy http://jci.me/77361

Bone biology Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification Osteoclast formation

Masato Yuasa, Nicholas A. Mignemi, Jeffry S. Nyman, Craig L. Duvall, Herbert S. Schwartz, Atsushi Okawa, Toshitaka Yoshii, Gourab Bhattacharjee, Chenguang Zhao, Jesse E. Bible, William T. Obremskey, Matthew J. Flick, Jay L. Degen, Joey V. Barnett, Justin M.M. Cates, and Jonathan G. Schoenecker http://jci.me/80313

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis Takahide Tohmonda, Masaki Yoda, Takao Iwawaki, Morio Matsumoto, Masaya Nakamura, Katsuhiko Mikoshiba, Yoshiaki Toyama, and Keisuke Horiuchi http://jci.me/76765

Cardiology Transcription factor ISL1 is essential for pacemaker development and function ISL1 in pacemaker cells

Xingqun Liang, Qingquan Zhang, Paola Cattaneo, Shaowei Zhuang, Xiaohui Gong, Nathanael J. Spann, Cizhong Jiang, Xinkai Chao, Xiaodong Zhao, Xiaoli Zhang, Lei Bu, Gang Wang, H.S. Vincent Chen, Tao Zhuang, Jie Yan, Peng Geng, Lina Luo, Indroneal Banerjee, Yihan Chen, Christopher K. Glass, Alexander C. Zambon, Ju Chen, Yunfu Sun, and Sylvia M. Evans http://jci.me/68257

T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients Stephen E. Boag, Rajiv Das, Evgeniya V. Shmeleva, Alan Bagnall, Mohaned Egred, Nicholas Howard, Karim Bennaceur, Azfar Zaman, Bernard Keavney, and Ioakim Spyridopoulos http://jci.me/80055

Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction Geoffrey de Couto, Wenxie Liu, Eleni Tseliou, Baiming Sun, Nupur Makkar, Hideaki Kanazawa, Moshe Arditi, and Eduardo Marbán http://jci.me/81321 Cardiac macrophages

With related Commentary by Nikolaos G. Frangogiannis More, p. 8

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Research articles in the current issue of the JCI

Cell biology MicroRNA-132 enhances transition from inflammation to proliferation during wound healing miR-132 in wounds

Dongqing Li, Aoxue Wang, Xi Liu, Florian Meisgen, Jacob Grünler, Ileana R. Botusan, Sampath Narayanan, Erdem Erikci, Xi Li, Lennart Blomqvist, Lei Du, Andor Pivarcsi, Enikö Sonkoly, Kamal Chowdhury, Sergiu-Bogdan Catrina, Mona Ståhle, and Ning Xu Landén http://jci.me/79052

Clinical trials Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients Mark R. Rigby, Kristina M. Harris, Ashley Pinckney, Linda A. DiMeglio, Marc S. Rendell, Eric I. Felner, Jean M. Dostou, Stephen E. Gitelman, Kurt J. Griffin, Eva Tsalikian, Peter A. Gottlieb, Carla J. Greenbaum, Nicole A. Sherry, Wayne V. Moore, Roshanak Monzavi, Steven M. Willi, Philip Raskin, Lynette Keyes-Elstein, S. Alice Long, Sai Kanaparthi, Noha Lim, Deborah Phippard, Carol L. Soppe, Margret L. Fitzgibbon, James McNamara, Gerald T. Nepom, Mario R. Ehlers, and the Immune Tolerance Network (ITN) T1DAL Study Group http://jci.me/81722 More, p. 9

Endocrinology Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic β cell insufficiency Adipocyte perilipin

Damaris N. Lorenzo, Jane A. Healy, Janell Hostettler, Jonathan Davis, Jiayu Yang, Chao Wang, Hans Ewald Hohmeier, Mingjie Zhang, and Vann Bennett http://jci.me/81317 More, p. 6

Genetics Med12 gain-of-function mutation causes leiomyomas and genomic instability

Priya Mittal, Yong-hyun Shin, Svetlana A. Yatsenko, Carlos A. Castro, Urvashi Surti, and Aleksandar Rajkovic http://jci.me/81534 More, p. 9

Hematology Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells Granulocytic differentiation

Ramesh C. Nayak, Lisa R. Trump, Bruce J. Aronow, Kasiani Myers, Parinda Mehta, Theodosia Kalfa, Ashley M. Wellendorf, C. Alexander Valencia, Patrick J. Paddison, Marshall S. Horwitz, H. Leighton Grimes, Carolyn Lutzko, and Jose A. Cancelas http://jci.me/80924

Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III Jenny Björkqvist, Steven de Maat, Urs Lewandrowski, Antonio Di Gennaro, Chris Oschatz, Kai Schönig, Markus M. Nöthen, Christian Drouet, Hal Braley, Marc W. Nolte, Albert Sickmann, Con Panousis, Coen Maas, and Thomas Renné http://jci.me/77139 More, p. 11

Immunology Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease Neil E. McCarthy, Charlotte R. Hedin, Theodore J. Sanders, Protima Amon, Inva Hoti, Ibrahim Ayada, Vidya Baji, Edward M. Giles, Martha Wildemann, Zora Bashir, Kevin Whelan, Ian Sanderson, James O. Lindsay, and Andrew J. Stagg http://jci.me/80840 More, p. 9 the journal of clinical investigation

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Research articles in the current issue of the JCI

Nephrology IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease Acute kidney transplant rejection

Jea-Hyun Baek, Rui Zeng, Julia Weinmann-Menke, M. Todd Valerius, Yukihiro Wada, Amrendra K. Ajay, Marco Colonna, and Vicki R. Kelley http://jci.me/81166

Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis Rafael Kramann, Susanne V. Fleig, Rebekka K. Schneider, Steven L. Fabian, Derek P. DiRocco, Omar Maarouf, Janewit Wongboonsin, Yoichiro Ikeda, Dirk Heckl, Steven L. Chang, Helmut G. Rennke, Sushrut S. Waikar, and Benjamin D. Humphreys http://jci.me/74929

Gli1-KO kidney

More, p. 12

Neuroscience Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals Leandro F. Vendruscolo, David Estey, Vivian Goodell, Lauren G. Macshane, Marian L. Logrip, Joel E. Schlosburg, M. Adrienne McGinn, Eva R. Zamora-Martinez, Joseph K. Belanoff, Hazel J. Hunt, Pietro P. Sanna, Olivier George, George F. Koob, Scott Edwards, and Barbara J. Mason http://jci.me/79828 More, p. 10

B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability Gunnar Houge, Dorien Haesen, Lisenka E.L.M. Vissers, Sarju Mehta, Michael J. Parker, Michael Wright, Julie Vogt, Shane McKee, John L. Tolmie, Nuno Cordeiro, Tjitske Kleefstra, Marjolein H. Willemsen, Margot R.F. Reijnders, Siren Berland, Eli Hayman, Eli Lahat, Eva H. Brilstra, Koen L.I. van Gassen, Evelien Zonneveld-Huijssoon, Charlotte I. de Bie, Alexander Hoischen, Evan E. Eichler, Rita Holdhus, Vidar M. Steen, Stein Ove Døskeland, Matthew E. Hurles, David R. FitzPatrick, the Deciphering Developmental Disorders (DDD) study, and Veerle Janssens http://jci.me/79860

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome Navasona Krishnan, Keerthi Krishnan, Christopher R. Connors, Meng S. Choy, Rebecca Page, Wolfgang Peti, Linda Van Aelst, Stephen D. Shea, and Nicholas K. Tonks http://jci.me/80323 Dorsal root ganglion neurons

With related Commentary by Lutz Tautz More, p. 10

Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion Gang Chen, Chul-Kyu Park, Rou-Gang Xie, and Ru-Rong Ji http://jci.me/80883 More, p. 10

Oncology Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma Emily Z. Keung, Kadir C. Akdemir, Ghadah A. Al Sannaa, Jeannine Garnett, Dina Lev, Keila E. Torres, Alexander J. Lazar, Kunal Rai, and Lynda Chin http://jci.me/77976 More, p. 8

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Research articles in the current issue of the JCI

Pulmonology High IFN-γ and low SLPI mark severe asthma in mice and humans Severe asthma in murine lung

Mahesh Raundhal, Christina Morse, Anupriya Khare, Timothy B. Oriss, Jadranka Milosevic, John Trudeau, Rachael Huff, Joseph Pilewski, Fernando Holguin, Jay Kolls, Sally Wenzel, Prabir Ray, and Anuradha Ray http://jci.me/80911 More, p. 11

Helicobacter urease–induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma Katrin N. Koch, Mara L. Hartung, Sabine Urban, Andreas Kyburz, Anna S. Bahlmann, Judith Lind, Steffen Backert, Christian Taube, and Anne Müller http://jci.me/79337

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease Yang Zhou, Chuan Hua He, Erica L. Herzog, Xueyan Peng, Chang-Min Lee, Tung H. Nguyen, Mridu Gulati, Bernadette R. Gochuico, William A. Gahl, Martin L. Slade, Chun Geun Lee, and Jack A. Elias http://jci.me/79792

Vaccines Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses Michelle Meyer, Tania Garron, Ndongala M. Lubaki, Chad E. Mire, Karla A. Fenton, Curtis Klages, Gene G. Olinger, Thomas W. Geisbert, Peter L. Collins, and Alexander Bukreyev http://jci.me/81532 More, p. 12

Vascular biology GATA2 is required for lymphatic vessel valve development and maintenance

Lymphatic vessel valves

Jan Kazenwadel, Kelly L. Betterman, Chan-Eng Chong, Philippa H. Stokes, Young K. Lee, Genevieve A. Secker, Yan Agalarov, Cansaran Saygili Demir, David M. Lawrence, Drew L. Sutton, Sebastien P. Tabruyn, Naoyuki Miura, Marjo Salminen, Tatiana V. Petrova, Jacqueline M. Matthews, Christopher N. Hahn, Hamish S. Scott, and Natasha L. Harvey http://jci.me/78888 With related Commentary by Tsutomu Kume More, p. 7

Lymph flow regulates collecting lymphatic vessel maturation in vivo Daniel T. Sweet, Juan M. Jiménez, Jeremy Chang, Paul R. Hess, Patricia Mericko-Ishizuka, Jianxin Fu, Lijun Xia, Peter F. Davies, and Mark L. Kahn http://jci.me/79386 With related Commentary by Tsutomu Kume Mesenteric lymphatics

More, p. 7

Flow-dependent expression of ectonucleotide tri(di)phosphohydrolase-1 and suppression of atherosclerosis Yogendra Kanthi, Matthew C. Hyman, Hui Liao, Amy E. Baek, Scott H. Visovatti, Nadia R. Sutton, Sascha N. Goonewardena, Mithun K. Neral, Hanjoong Jo, and David J. Pinsky http://jci.me/79514

P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction ShengPeng Wang, András Iring, Boris Strilic, Julián Albarrán Juárez, Harmandeep Kaur, Kerstin Troidl, Sarah Tonack, Joachim C. Burbiel, Christa E. Müller, Ingrid Fleming, Jon O. Lundberg, Nina Wettschureck, and Stefan Offermanns http://jci.me/81067 More, p. 7

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Research

Editor’s picks Ankyrin-B variant disrupts glucose uptake and promotes adiposity Environmental triggers and genetic predisposition can both contribute to the development of type 2 diabetes. While a small percentage of type 2 diabetes cases are associated with known common SNPs, less frequent variants also are likely to influence disease susceptibility in many cases. In this issue of the JCI, Damaris Lorenzo and colleagues explore how mutations in ankyrin-B (AnkB) affect insulin sensitivity and adiposity. Using knockin mouse models of two AnkB variants that occur in the human population, they demonstrate that animals homozygous for the R1788W mutation have reduced insulin secretion at a young age and increased adiposity at older ages or when fed a high-fat diet. Interestingly, young animals had normal glucose levels, despite reduced insulin production, due to elevated glucose uptake into muscle and adipose tissue. Mechanistically, the research team showed that the R1788W mutation was expressed at lower levels and had impaired function. The R1778W mutation led to increased cell surface levels of glucose transporter 4 (GLUT4), which is dynamically regulated in response to insulin, due to a disruption in AnkB-mediated endocytosis of GLUT4. Though this initially protected young animals from low insulin levels, with age and sustained elevation in glucose uptake, the mice gained weight and developed insulin resistance. This study provides new insights into the mechanisms by which rare variants in AnkB promote metabolic dysfunction. The accompanying image is an isosurface rendering of 3D confocal images showing enlarged lipid droplets (green) in differentiated adipocytes expressing the R1788W human AnkB variant (red), with nuclei shown in blue. Image credit: Damaris Lorenzo. 6

Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic β cell insufficiency Damaris N. Lorenzo, Jane A. Healy, Janell Hostettler, Jonathan Davis, Jiayu Yang, Chao Wang, Hans Ewald Hohmeier, Mingjie Zhang, and Vann Bennett http://jci.me/81317

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Research | Editor’s picks

vascular biology

Identification of factors that mediate lymphatic valve development In this issue, two groups of investigators identify factors that are critical for the development of lymphatic vasculature valves. Valves, which largely develop in regions of disturbed lymph flow, are required to prevent backflow and maintain lymph circulation. Natasha Harvey and colleagues demonstrate that lymphedema-associated mutations in the transcription factor GATA2 block its ability to bind an enhancer element upstream of PROX1, the master regulator of the lymphatic vasculature. Selective inactivation of Gata2 in mice impaired valve development and maintenance. Mark Kahn and colleagues investigated the role of fluid shear forces in lymphatic vessel development. Using a murine model of impaired lymph flow, they show that decreased fluid shear force abrogates the development of lymphatic valves and collecting vessel maturation without affecting primary lymphatic vessel growth (see the accompanying image). Both groups found that low levels of oscillatory shear stress induce expression of genes required for valve development, including GATA2. In the accompanying Commentary, Tsutomu Kume discusses how these studies implicate lymph flow–induced GATA2 upregulation as a critical requirement for the development of valves in the lymphatic vasculature. Related Research GATA2 is required for lymphatic vessel valve development and maintenance Jan Kazenwadel, Kelly L. Betterman, Chan-Eng Chong, Philippa H. Stokes, Young K. Lee, Genevieve A. Secker, Yan Agalarov, Cansaran Saygili Demir, David M. Lawrence, Drew L. Sutton, Sebastien P. Tabruyn, Naoyuki Miura, Marjo Salminen, Tatiana V. Petrova, Jacqueline M. Matthews, Christopher N. Hahn, Hamish S. Scott, and Natasha L. Harvey http://jci.me/78888 Lymph flow regulates collecting lymphatic vessel maturation in vivo Daniel T. Sweet, Juan M. Jiménez, Jeremy Chang, Paul R. Hess, Patricia Mericko-Ishizuka, Jianxin Fu, Lijun Xia, Peter F. Davies, and Mark L. Kahn http://jci.me/79386 Related Commentary Lymphatic vessel development: fluid flow and valve-forming cells Tsutomu Kume http://jci.me/83189

Fluid shear stress induces vasodilation through a P2Y2 receptor–mediated pathway Vascular tone and blood pressure are regulated by the fluid shear stress generated by blood flow. ShengPeng Wang and colleagues demonstrate that fluid shear stress induces release of ATP from endothelial cells to activate the purinergic receptor P2Y2, a GPCR that activates the G proteins Gq/G11 on endothelial cells. Activation of this pathway induces release of intracellularly stored calcium, activation of endothelial nitric oxide synthase (eNOS), SRC, and AKT, and phosphorylation of PECAM-1 and VEGFR-2. Wang and colleagues generated mice with induced, endothelium-specific P2Y2 or Gq/G11 deficiency and found that these animals lacked flow-induced vasodilation, resulting in

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reduced eNOS activation and subsequent hypertension. These results demonstrate that P2Y2 and Gq/G11 are critical mediators of basal vascular tone and blood pressure. P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction ShengPeng Wang, András Iring, Boris Strilic, Julián Albarrán Juárez, Harmandeep Kaur, Kerstin Troidl, Sarah Tonack, Joachim C. Burbiel, Christa E. Müller, Ingrid Fleming, Jon O. Lundberg, Nina Wettschureck, and Stefan Offermanns http://jci.me/81067

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Research | Editor’s picks

cardiology

Cardiospheres direct myocardial macrophages to a cardioprotective phenotype Cardiospheres are self-assembling, multicellular clusters that contain primitive, proliferating cells, mesenchymal/stromal cells, and differentiating cells that express cardiomyocyte proteins. Administration of cardiosphere-derived cells (CDCs) reduces infarct size and improves cardiac function after myocardial infarction (MI) in both humans and animal models. Using a rat model of ischemia/reperfusion-induced MI, Geoffrey de Couto and colleagues found that CDCs modify the myocardial leukocyte population, reducing the number of CD68+ macrophages and polarizing macrophages to a specific cardioprotective phenotype; clodronate-mediated depletion of macrophages abolished the protective effects of CDCs. Moreover, adoptive transfer of macrophages exposed to CDC-conditioned media recapitulated the effects of CDC administration (see the accompanying image), indicating that CDCs secrete factors that mediate macrophage polarization. In the accompanying Commentary, Nikolaos Frango­ giannis discusses how these studies demonstrate a critical role for macrophages in mediating CDC-induced cardioprotection. Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction Geoffrey de Couto, Wenxie Liu, Eleni Tseliou, Baiming Sun, Nupur Makkar, Hideaki Kanazawa, Moshe Arditi, and Eduardo Marbán http://jci.me/81321 Related Commentary Emerging roles for macrophages in cardiac injury: cytoprotection, repair, and regeneration Nikolaos G. Frangogiannis http://jci.me/83191

oncology

Epigenetic marks distinguish liposarcoma subtypes Liposarcoma (LPS) is a common form of soft tissue sarcoma that can be divided into four subtypes, with well-differentiated (WDLPS) and dedifferentiated (DDLPS) being the most common. Emily Keung and colleagues examined the contribution of epigenetic modifications to the development of these two subtypes by profiling nine epigenetic marks in 151 patients. They found that DDLPS tumors exhibited elevated levels of trimethylated lysine 9 on histone 3 (H3K9me3). Integrated ChIP-sequencing and gene expression analyses revealed that increased H3K9me3 levels decreased the expression of genes involved in cellular migration and differentiation, including Krüppel-like factor 6 (KLF6). Pharmacological inhibition of

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H3K9 methylation decreased DDLPS proliferation and increased factors that mediate adipogenesis. These effects were partially replicated by overexpression of KLF6 (see the accompanying image). These data indicate that epigenetic changes may underlie the transition from WDLPS to DDLPS. Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma Emily Z. Keung, Kadir C. Akdemir, Ghadah A. Al Sannaa, Jeannine Garnett, Dina Lev, Keila E. Torres, Alexander J. Lazar, Kunal Rai, and Lynda Chin http://jci.me/77976

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Research | Editor’s picks

clinical trials

Alefacept treatment of newly diagnosed type 1 diabetes patients Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic β islets. Mark Rigby and colleagues report on a multicenter, randomized, double-blind, placebo-controlled clinical trial in which patients with newly diagnosed T1D were treated with alefacept, an immunosuppressive drug that inhibits activation and induces apoptosis of effector memory T cells, which are thought to be primarily responsible for β cell destruction. Patients received two 12-week courses of i.m. injections, separated by a 12-week pause. Fifteen months after the last treatment, patients receiving alefacept had greater C-peptide secretion, required less exogenous insulin, and had fewer hypoglycemic events compared with patients receiving placebo. Additionally, alefacept treatment depleted central memory and effector memory T cells. These results demonstrate that alefacept treatment may benefit newly diagnosed T1D patients. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients Mark R. Rigby, Kristina M. Harris, Ashley Pinckney, Linda A. DiMeglio, Marc S. Rendell, Eric I. Felner, Jean M. Dostou, Stephen E. Gitelman, Kurt J. Griffin, Eva Tsalikian, Peter A. Gottlieb, Carla J. Greenbaum, Nicole A. Sherry, Wayne V. Moore, Roshanak Monzavi, Steven M. Willi, Philip Raskin, Lynette Keyes-Elstein, S. Alice Long, Sai Kanaparthi, Noha Lim, Deborah Phippard, Carol L. Soppe, Margret L. Fitzgibbon, James McNamara, Gerald T. Nepom, Mario R. Ehlers, and the Immune Tolerance Network (ITN) T1DAL Study Group http://jci.me/81722

genetics

A cause for genetic instability in uterine leiomyomas Uterine leiomyomas are benign, monoclonal tumors that are the single largest cause of hysterectomy. Leiomyomas frequently have karyotypic abnormalities. Additionally, whole-exome sequencing has identified a number of heterozygous somatic mutations in mediator complex subunit 12 (MED12), which occur in roughly 70% of patients. Priya Mittal, Yong-hyun Shin, and colleagues examined the role of MED12 in the pathogenesis of leiomyoma by generating a mouse model that conditionally expresses a common Med12 missense variant, Med12 c.131G>A. Expression of this variant caused leiomyomas and hyperplasia on either a WT or Med12-KO background. Leiomyomas induced by mutant MED12 developed chromosomal rearrangements similar to those seen in human leiomyomas. The accompanying image shows uteri from control mice (left) and from mice expressing Med12 c.131G>A (right). Med12 gain-of-function mutation causes leiomyomas and genomic instability Priya Mittal, Yong-hyun Shin, Svetlana A. Yatsenko, Carlos A. Castro, Urvashi Surti, and Aleksandar Rajkovic http://jci.me/81534

immunology

Defining the role of Vδ2 T cells in Crohn’s disease Unconventional lymphocytes expressing the Vγ9Vδ2 T cell receptor (Vδ2 T cells) recognize nonpeptide metabolites known as phosphoantigens, which are produced by bacteria and tumor cells and mediate host protection against microbial infections, lymphoproliferative disorders, and cancer. Neil McCarthy and colleagues examined the phenotype and functions of Vδ2 T cells in blood and colon from Crohn’s disease patients (CD patients) and healthy controls. Compared with healthy controls, Vδ2 T cells from CD patients displayed increased gut-homing potential, depletion of circulating proinflammatory cells, and increased TNF-α production in colon, which was impaired by blockade of retinoic acid receptor-α. Treatment with the immunosuppressive drug azathioprine (AZA), which is used to manage moderate to severe CD, selectively ablated Vδ2 T cells. These studies indicate that Vδ2 T cell impairment may contribute to the therapeutic effects of AZA in CD; however, AZA-induced loss of these cells may contribute to the increased incidence of lymphoma in CD patients. Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease Neil E. McCarthy, Charlotte R. Hedin, Theodore J. Sanders, Protima Amon, Inva Hoti, Ibrahim Ayada, Vidya Baji, Edward M. Giles, Martha Wildemann, Zora Bashir, Kevin Whelan, Ian Sanderson, James O. Lindsay, and Andrew J. Stagg http://jci.me/80840

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Research | Editor’s picks

neuroscience

Mifepristone decreases alcohol intake in alcoholdependent rats and humans

Pharmacological inhibition of PTP1B ameliorates Rett syndrome in mice

Alcoholism is a complex psychiatric condition with few effective treatments. In previous studies, Leandro F. Vendruscolo and colleagues demonstrated that dysregulation of the neuroendocrine stress system, including changes in brain glucocorticoid receptor (GR) expression, were associated with compulsive-like alcohol intake in rats. In this issue, Vendruscolo and colleagues demonstrate that administration of the GR antagonist mifepristone reduces alcohol intake in alcohol-dependent rats, but not in nondependent animals. In a double-blind study of 56 alcoholdependent human subjects, mifepristone treatment substantially reduced alcohol craving and alcohol consumption compared with placebo. These results support further study of mifepristone as a therapeutic strategy for the treatment of alcoholism.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder predominately caused by mutations of methyl-CpG–binding protein 2 (MECP2). Navasona Krishnan and colleagues demonstrate that PTPN1, which encodes the phosphatase PTP1B, is a direct target of MECP2 and that PTP1B levels were markedly increased in both Mecp2-mutant mice and fibroblasts from RTT patients. Treatment with PTP1B inhibitors increased the lifespan of male RTT mice (Mecp2–/y) and improved the performance of female RTT mice (Mecp2–/+) in behavioral assays. Mechanistically, PTP1B inhibition enhanced phosphorylation of tropomyosin receptor kinase B (TRKB), which mediates brain-derived neurotrophic factor (BDNF) signaling. In the accompanying Commentary, Lutz Tautz discusses how these results indicate that PTP1B inhibition is a potential therapeutic strategy for the treatment of RTT.

Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals Leandro F. Vendruscolo, David Estey, Vivian Goodell, Lauren G. Macshane, Marian L. Logrip, Joel E. Schlosburg, M. Adrienne McGinn, Eva R. Zamora-Martinez, Joseph K. Belanoff, Hazel J. Hunt, Pietro P. Sanna, Olivier George, George F. Koob, Scott Edwards, and Barbara J. Mason http://jci.me/79828

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome Navasona Krishnan, Keerthi Krishnan, Christopher R. Connors, Meng S. Choy, Rebecca Page, Wolfgang Peti, Linda Van Aelst, Stephen D. Shea, and Nicholas K. Tonks http://jci.me/80323 Related Commentary PTP1B: a new therapeutic target for Rett syndrome Lutz Tautz http://jci.me/83192

Bone marrow stromal cells block neuropathic pain Neuropathic pain is a complex disease state triggered by insult to the nervous system that results in hypersensitivity. Gang Chen and colleagues report that a local, intrathecal injection of bone marrow stromal cells (BMSCs) following lumbar puncture alleviated allodynia and hyperalgesia in two different murine models of neuropathic pain. After recruitment to the dorsal root ganglion (DRG) by CXCL12 secreted at the site of injury, BMSCs can survive for up to two months (see the accompanying image). Analgesic effects were mediated by BMSC secretion of TGF-β1 into the cerebrospinal fluid to suppress injury-induced synaptic plasticity and neuroinflammation in the spinal cord. These effects could be replicated with exogenous TGF-β1 and were blocked by TGF-β1–neutralizing antibodies. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion Gang Chen, Chul-Kyu Park, Rou-Gang Xie, and Ru-Rong Ji http://jci.me/80883

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Research | Editor’s picks

pulmonology

Distinct immune response distinguishes severe asthma Unlike mild-moderate asthma (MMA), severe asthma (SA) is poorly controlled by corticosteroids, suggesting that different immune mechanisms contribute to SA. Mahesh Raundhal and colleagues analyzed broncholalveolar lavage cells from MMA and SA patients and found that SA patients had a greater IFN-γ/Th1 immune response compared with MMA patients, which was accompanied by low IL-17/Th2 responses. In a murine model of SA, loss of Ifng blocked airway hyperresponsiveness (AHR) without a change in airway inflammation (see the accompanying image), while loss of Il17 reduced airway inflammation, but did not impair AHR. IFN-γ levels were inversely correlated with secretory leukocyte protease inhibitor (SLPI), which is downregulated in both humans and mice with SA. Increasing expression of SLP1 in mice reduced AHR. These data characterize aspects of the immune response that distinguish SA from MMA.

High IFN-γ and low SLPI mark severe asthma in mice and humans Mahesh Raundhal, Christina Morse, Anupriya Khare, Timothy B. Oriss, Jadranka Milosevic, John Trudeau, Rachael Huff, Joseph Pilewski, Fernando Holguin, Jay Kolls, Sally Wenzel, Prabir Ray, and Anuradha Ray http://jci.me/80911

hematology

Loss of factor XII glycosylation underlies hereditary angioedema type III Hereditary angioedema type III (HAEIII) is an inherited, life-threatening swelling disorder that results from increased vascular permeability caused by excessive formation of the proinflammatory peptide hormone bradykinin. Plasma protease factor XII (FXII) initiates bradykinin formation via the kallikrein-kinin system, and point mutations in FXII are associated with HAEIII. Jenny Björkqvist and colleagues demonstrate that mutant FXII is defective in a mucin-type Thr309-linked glycosylation, which increases the contact-mediated autoactivation of FXII zymogen and leads to increased bradykinin formation. Importantly, both mice expressing mutant forms of FXII and a humanized

HAEIII mouse model exhibited increased microvascular leakage. Administration of FXII-neutralizing antibodies blocked bradykinin expression in HAEIII patient plasma and attenuated edema in HAEIII mice. These findings identify FXII inhibition as a potential therapeutic strategy in HAEIII. The accompanying image shows vascular leakage in (right to left) HAEIII mice with WT FXII and mutant FXII as well as mutant FXII mice treated with a plasma kallikrein inhibitor or the FXII-neutralizing antibody 3F7.

the journal of clinical investigation

Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III Jenny Björkqvist, Steven de Maat, Urs Lewandrowski, Antonio Di Gennaro, Chris Oschatz, Kai Schönig, Markus M. Nöthen, Christian Drouet, Hal Braley, Marc W. Nolte, Albert Sickmann, Con Panousis, Coen Maas, and Thomas Renné http://jci.me/77139

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Research | Editor’s picks

nephrology

Targeting myofibroblast proliferation in kidney fibrosis Interstitial fibrosis is a key feature of chronic kidney disease (CKD), a process mediated by myofibroblasts, which secrete matrix proteins. The hedgehog signaling pathway transcription factors GLI1 and GLI2 are expressed in myofibroblast progenitors, but their role in fibrosis is not well understood. Using murine models of kidney disease, Rafael Kramann and colleagues demonstrate that GLI2, but not GLI1, drives cell-cycle proliferation in myofibroblasts. Either selective KO of Gli2 or suppression of the hedgehog pathway through expression of the transcriptional repressor GLI3 in myofibroblast progenitors induced cell-cycle arrest and abrogated fibrosis. Additionally, treatment with darinaparsin, which is currently in clinical trials as an antineoplastic agent, reduced GLI2 protein levels to promote cell-cycle arrest and reduce fibrosis (see the accompanying image). Kramann and colleagues found that GLI1 and GLI2 are overexpressed in human kidney fibrosis, indicating that GLI2 may be a suitable therapeutic target in CKD.

Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis Rafael Kramann, Susanne V. Fleig, Rebekka K. Schneider, Steven L. Fabian, Derek P. DiRocco, Omar Maarouf, Janewit Wongboonsin, Yoichiro Ikeda, Dirk Heckl, Steven L. Chang, Helmut G. Rennke, Sushrut S. Waikar, and Benjamin D. Humphreys http://jci.me/74929

vaccines

Aerosolized Ebola vaccine protects primates In this issue, Michelle Meyer and colleagues demonstrate that an aerosolized formulation of an Ebola vaccine protects rhesus macaques. Two groups of animals were vaccinated via the respiratory tract with either an aerosolized or liquid formulation of a parainfluenza virus type 3– vectored vaccine expressing the EBOV glycoprotein. A third group of animals was vaccinated i.m. with a Venezuelan equine encephalitis replicon vaccine expressing the EBOV glycoprotein. The aerosolized vaccine induced an EBOV-specific cellular response that was greatest in lungs and also elicited antibody titers and CD4+ T cell responses that were greater than or equal to the titers induced by the liquid formulation. The respiratory tract vaccines induced more robust cellular and humoral responses than the intramuscular vaccine. Importantly, a single vaccination with the aerosolized formulation conferred 100% protection to macaques exposed to EBOV. These studies demonstrate the safety, immunogenicity, and protective efficacy of an aerosolized EBOV vaccine and suggest that this approach should be tested in clinical trials. Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses Michelle Meyer, Tania Garron, Ndongala M. Lubaki, Chad E. Mire, Karla A. Fenton, Curtis Klages, Gene G. Olinger, Thomas W. Geisbert, Peter L. Collins, and Alexander Bukreyev http://jci.me/81532

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Features

conversations with giants in medicine

Stuart Kornfeld Dr. Stuart Kornfeld is the David C. and Betty Farrell Distinguished Professor of Medicine at Washington University in St. Louis. He is best known for his work elucidating the processes governing lysosome biogenesis. His research continues to uncover roles for oligosaccharide biosynthesis, processing, and maturation in mediating proper folding and transport of proteins. In an interview with JCI Editor-at-Large Ushma Neill, Kornfeld discusses how his first biochemistry course, taught by Carl and Gerty Cori, and his work as a postdoctoral researcher in Luis Glaser’s lab led to his interest in the role of sugar moieties in cellular physiology. Kornfeld also discusses his early work with postdoctoral fellows Ira Tabas and Ajit Varki and graduate student Marc Reitman in characterizing the trafficking of lysosomal proteins. Finally, Kornfeld addresses the importance of mentors in the development of physician-scientists. http://jci.me/82628

review

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MECP2 disorders: combining patient, murine, and molecular data Rett syndrome (RTT) and MECP2 duplication syndrome result from loss or gain of function, respectively, of methyl-CpG– binding protein 2 (MECP2). Both disorders are characterized by intellectual disability, autism, and developmental regression. In murine models of RTT, neuronal dysfunction can be reversed by restoration of MECP2 function. Conversely, overexpression of MECP2 replicates human MECP2 duplication syndrome, highlighting the sensitivity of neurons to MECP2 levels. In this Review, Huda Zoghbi and colleagues detail the clinical profiles of MECP2 disorders and discuss knowledge gained from studies of the molecular function of MECP2 as well as from murine models of RTT. Finally, they discuss the impact of preclinical and clinical studies on the development of therapeutic strategies for MECP2 disorders. MECP2 disorders: from the clinic to mice and back Laura Marie Lombardi, Steven Andrew Baker, and Huda Yahya Zoghbi http://jci.me/78167

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