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NOTCH mediates bone fracture repair 7

Schwann cells promote cancer cell invasion 11

Review series: extracellular vesicles edited by Laurence Zitvogel 13

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extracellular vesicles in vascular calcification

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April 2016

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This MonthApril 2016

Extracellular vesicle–mediated vascular calcification is regulated by sortilin

On the JCI cover

With age, many individuals will develop vascular calcification, which reduces arterial elasticity and is associated with increased risk of cardiovascular complications. Previous studies have demonstrated that smooth muscle cells express several genes involved in bone formation, resulting in the deposition of a calcium-mineralized matrix. Smooth muscle cells also release extracellular vesicles that contribute to calcification, but the mechanisms governing this process have not been clear. In this issue of the JCI, Elena Aikawa and colleagues report that the multiligand sorting receptor sortilin regulates loading of tissue

nonspecific alkaline phosphatase (TNAP) into extracellular vesicles, which promotes calcification. They found that sortilin levels are elevated in calcified human atheroma and in a mouse model of calcified arteries. Further, mice with genetic loss of sortilin had decreased arterial calcification. Mass spectrometric analysis of sortilin-associated proteins revealed an interaction with TNAP, and subsequent studies showed that sortilin promotes TNAP activity in extracellular vesicles and microcalcification in cultured smooth muscle cells. Additionally, the research team found that smooth muscle cell calcification required Rab11, which regulates vesicle exocytosis, as well as phosphorylation of the C-termainal tail of sortilin. These findings collectively uncover a critical role for sortilin in vascular calcification induced by extracellular vesicles. The accompanying image is a density-dependent color scanning electron micrograph of a calcified human carotid artery atherosclerotic plaque. Dense, calcified areas are shown in orange, and less dense components of the plaque are shown in green. Image credit: Sergio Bertazzo.

Sortilin mediates vascular calcification via its recruitment into extracellular vesiclesClaudia Goettsch, Joshua D. Hutcheson, Masanori Aikawa, Hiroshi Iwata, Tan Pham, Anders Nykjaer, Mads Kjolby, Maximillian Rogers, Thomas Michel, Manabu Shibasaki, Sumihiko Hagita, Rafael Kramann, Daniel J. Rader, Peter Libby, Sasha A. Singh, and Elena Aikawa http://jci.me/80851

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Research articles in the current issue of the JCI

AIDS/HIVMacrophages sustain HIV replication in vivo independently of T cellsJenna B. Honeycutt, Angela Wahl, Caroline Baker, Rae Ann Spagnuolo, John Foster, Oksana Zakharova, Stephen Wietgrefe, Carolina Caro-Vegas, Victoria Madden, Garrett Sharpe, Ashley T. Haase, Joseph J. Eron, and J. Victor Garcia http://jci.me/84456

More, p. 6

Bone biologyNOTCH signaling in skeletal progenitors is critical for fracture repairCuicui Wang, Jason A. Inzana, Anthony J. Mirando, Yinshi Ren, Zhaoyang Liu, Jie Shen, Regis J. O’Keefe, Hani A. Awad, and Matthew J. Hilton http://jci.me/80672

More, p. 7

EndocrinologyPI3-kinase mutation linked to insulin and growth factor resistance in vivoJonathon N. Winnay, Marie H. Solheim, Ercument Dirice, Masaji Sakaguchi, Hye-Lim Noh, Hee Joon Kang, Hirokazu Takahashi, Kishan K. Chudasama, Jason K. Kim, Anders Molven, C. Ronald Kahn, and Pål R. Njølstad http://jci.me/84005

GeneticsModulation of LMNA splicing as a strategy to treat prelamin A diseasesJohn M. Lee, Chika Nobumori, Yiping Tu, Catherine Choi, Shao H. Yang, Hea-Jin Jung, Timothy A. Vickers, Frank Rigo, C. Frank Bennett, Stephen G. Young, and Loren G. Fong http://jci.me/85908

With related Commentary by Elizabeth M. McNally and Eugene J. Wyatt

More, p. 8

HematologyRenal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietinNavid M. Farsijani, Qingdu Liu, Hanako Kobayashi, Olena Davidoff, Feng Sha, Joachim Fandrey, T. Alp Ikizler, Paul M. O’Connor, and Volker H. Haase http://jci.me/74997

RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferationJayanth Kumar Palanichamy, Tiffany M. Tran, Jonathan M. Howard, Jorge R. Contreras, Thilini R. Fernando,

Timothy Sterne-Weiler, Sol Katzman, Masoud Toloue, Weihong Yan, Giuseppe Basso, Martina Pigazzi, Jeremy R. Sanford, and Dinesh S. Rao http://jci.me/80046

Fracture union

Aortic progerin

Hepatic erythropoietin

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Research articles in the current issue of the JCI

ImmunologyDisabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammationSamantha E. Adamson, Rachael Griffith, Radim Moravec, Subramanian Senthivinayagam, Garren Montgomery, Wenshu Chen, Jenny Han, Poonam R. Sharma, Garrett R. Mullins, Stacey A. Gorski, Jonathan A. Cooper, Alexandra Kadl, Kyle Enfield, Thomas J. Braciale, Thurl E. Harris, and Norbert Leitinger http://jci.me/79590

More, p. 12

Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseasesNadine Dragin, Jacky Bismuth, Géraldine Cizeron-Clairac, Maria Grazia Biferi, Claire Berthault, Alain Serraf, Rémi Nottin, David Klatzmann, Ana Cumano, Martine Barkats, Rozen Le Panse, and Sonia Berrih-Aknin http://jci.me/81894

With related Commentary by Pearl Bakhru and Maureen A. Su

More, p. 12

H7N9 influenza virus neutralizing antibodies that possess few somatic mutationsNatalie J. Thornburg, Heng Zhang, Sandhya Bangaru, Gopal Sapparapu, Nurgun Kose, Rebecca M. Lampley, Robin G. Bombardi, Yingchun Yu, Stephen Graham, Andre Branchizio, Sandra M. Yoder, Michael T. Rock, C. Buddy Creech, Kathryn M. Edwards, David Lee, Sheng Li, Ian A. Wilson, Adolfo García-Sastre, Randy A. Albrecht, and James E. Crowe Jr. http://jci.me/85317

Muscle biologyUTX demethylase activity is required for satellite cell–mediated muscle regenerationHervé Faralli, Chaochen Wang, Kiran Nakka, Aissa Benyoucef, Soji Sebastian, Lenan Zhuang, Alphonse Chu, Carmen G. Palii, Chengyu Liu, Brendan Camellato, Marjorie Brand, Kai Ge, and F. Jeffrey Dilworth http://jci.me/83239

With related Commentary by Ling Liu and Thomas A. Rando

More, p. 8

NeuroscienceAstrocytes are central in the pathomechanisms of vanishing white matterStephanie Dooves, Marianna Bugiani, Nienke L. Postma, Emiel Polder, Niels Land, Stephen T. Horan, Anne-Lieke F. van Deijk, Aleid van de Kreeke, Gerbren Jacobs, Caroline Vuong, Jan Klooster, Maarten Kamermans, Joke Wortel, Maarten Loos, Lisanne E. Wisse, Gert C. Scheper, Truus E.M. Abbink, Vivi M. Heine, and Marjo S. van der Knaap http://jci.me/83908

More, p. 7

Dose-escalation study of octanoic acid in patients with essential tremorBernhard Voller, Emily Lines, Gayle McCrossin, Sule Tinaz, Codrin Lungu, George Grimes, Judith Starling, Gopal Potti, Peter Buchwald, Dietrich Haubenberger, and Mark Hallett http://jci.me/83621

OncologyLNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitorsYing Cheng, Kudakwashe Chikwava, Chao Wu, Haibing Zhang, Anchit Bhagat, Dehua Pei, John K. Choi, and Wei Tong http://jci.me/81468

VWM glial pathology

UTX inhibition in muscle

Tp53–/–Lnk–/– B cell leukemia

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OncologyLoss of gastrokine-2 drives premalignant gastric inflammation and tumor progressionTrevelyan R. Menheniott, Louise O’Connor, Yok Teng Chionh, Jan Däbritz, Michelle Scurr, Benjamin N. Rollo, Garrett Z. Ng, Shelley Jacobs, Angelique Catubig, Bayzar Kurklu, Stephen Mercer, Toshinari Minamoto, David E. Ong, Richard L. Ferrero, James G. Fox, Timothy C. Wang, Philip Sutton, Louise M. Judd, and Andrew S. Giraud http://jci.me/82655

More, p. 10

MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemiaSimone S. Riedel, Jessica N. Haladyna, Matthew Bezzant, Brett Stevens, Daniel A. Pollyea, Amit U. Sinha, Scott A. Armstrong, Qi Wei, Roy M. Pollock, Scott R. Daigle, Craig T. Jordan, Patricia Ernst, Tobias Neff, and Kathrin M. Bernt http://jci.me/80825

More, p. 10

Involvement of activation-induced cytidine deaminase in skin cancer developmentTaichiro Nonaka, Yoshinobu Toda, Hiroshi Hiai, Munehiro Uemura, Motonobu Nakamura, Norio Yamamoto, Ryo Asato, Yukari Hattori, Kazuhisa Bessho, Nagahiro Minato, and Kazuo Kinoshita http://jci.me/81522

Targeting prion-like protein doppel selectively suppresses tumor angiogenesisTaslim A. Al-Hilal, Seung Woo Chung, Jeong Uk Choi, Farzana Alam, Jooho Park, Seong Who Kim, Sang Yoon Kim,

Fakhrul Ahsan, In-San Kim, and Youngro Byun http://jci.me/83427

More, p. 11

Schwann cells induce cancer cell dispersion and invasionSylvie Deborde, Tatiana Omelchenko, Anna Lyubchik, Yi Zhou, Shizhi He, William F. McNamara, Natalya Chernichenko, Sei-Young Lee, Fernando Barajas, Chun-Hao Chen, Richard L. Bakst, Efsevia Vakiani, Shuangba He, Alan Hall, and Richard J. Wong http://jci.me/82658

With related Commentary by Salma H. Azam and Chad V. Pecot

More, p. 11

Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancyDongjun Lee, Ying-Hua Wang, Demetrios Kalaitzidis, Janani Ramachandran, Homare Eda, David B. Sykes, Noopur Raje, and David T. Scadden http://jci.me/84620

Thymic stromal lymphopoietin blocks early stages of breast carcinogenesisShadmehr Demehri, Trevor J. Cunningham, Sindhu Manivasagam, Kenneth H. Ngo, Sara Moradi Tuchayi, Rasika Reddy, Melissa A. Meyers, David G. DeNardo, and Wayne M. Yokoyama http://jci.me/83724

Research articles in the current issue of the JCI

Skin carcinogenesis

Schwann cell NCAM1

Gastrokine-2–deficient epithelium

TSLP-induced breast cancer

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Research articles in the current issue of the JCI

PulmonologyMacrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infectionChristin Peteranderl, Luisa Morales-Nebreda, Balachandar Selvakumar, Emilia Lecuona, István Vadász, Rory E. Morty, Carole Schmoldt, Julia Bespalowa, Thorsten Wolff, Stephan Pleschka, Konstantin Mayer, Stefan Gattenloehner, Ludger Fink, Juergen Lohmeyer, Werner Seeger, Jacob I. Sznajder, Gökhan M. Mutlu, G.R. Scott Budinger, and Susanne Herold http://jci.me/83931

With related Commentary by Rena Brauer and Peter Chen

More, p. 9

TransplantationMetabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantationHung D. Nguyen, Shilpak Chatterjee, Kelley M.K. Haarberg, Yongxia Wu, David Bastian, Jessica Heinrichs, Jianing Fu, Anusara Daenthanasanmak, Steven Schutt, Sharad Shrestha, Chen Liu, Honglin Wang, Hongbo Chi, Shikhar Mehrotra, and Xue-Zhong Yu http://jci.me/82587

More, p. 6

Alloantigen-specific regulatory T cells generated with a chimeric antigen receptorKatherine G. MacDonald, Romy E. Hoeppli, Qing Huang, Jana Gillies, Dan S. Luciani, Paul C. Orban, Raewyn Broady, and Megan K. Levings http://jci.me/82771

With related Commentary by Matthias Edinger

More, p. 6

Vascular biologySortilin mediates vascular calcification via its recruitment into extracellular vesiclesClaudia Goettsch, Joshua D. Hutcheson, Masanori Aikawa, Hiroshi Iwata, Tan Pham, Anders Nykjaer, Mads Kjolby, Maximillian Rogers, Thomas Michel, Manabu Shibasaki, Sumihiko Hagita, Rafael Kramann, Daniel J. Rader, Peter Libby, Sasha A. Singh, and Elena Aikawa http://jci.me/80851

More, p. 1

CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeabilityStoyan Ivanov, Joshua P. Scallan, Ki-Wook Kim, Kathrin Werth, Michael W. Johnson, Brian T. Saunders, Peter L. Wang, Emma L. Kuan, Adam C. Straub, Melissa Ouhachi, Erica G. Weinstein, Jesse W. Williams, Carlos Briseño, Marco Colonna, Brant E. Isakson, Emmanuel L. Gautier, Reinhold Förster, Michael J. Davis, Bernd H. Zinselmeyer, and Gwendalyn J. Randolph http://jci.me/84518

Matricellular protein CCN3 mitigates abdominal aortic aneurysmChao Zhang, Dustin van der Voort, Hong Shi, Rongli Zhang, Yulan Qing, Shuichi Hiraoka, Minoru Takemoto, Koutaro Yokote, Joseph V. Moxon, Paul Norman, Laure Rittié, Helena Kuivaniemi, G. Brandon Atkins, Stanton L. Gerson, Guo-Ping Shi, Jonathan Golledge, Nianguo Dong, Bernard Perbal, Domenick A. Prosdocimo, and Zhiyong Lin http://jci.me/82337

Influenza-infected lung

Matrix metalloproteinase activity

Calcified smooth muscle

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transplantation

Human macrophages independently sustain HIV viral replicationaids/hiv

JCI research | Editor’s picks

Targeting T cell metabolic alterations in graft-versus-host diseaseGraft-versus-host disease (GVhD), which is caused by alloreactive donor T cells, limits the success of allogeneic hematopoietic stem cell transplantation (HSCT). Though metabolic alterations are known to drive changes in T cell fate and function, little is known about T cell metabolic alterations in GVHD. Hung Nguyen and colleagues examined T cell metabolic profiles using two murine models of HSCT. They found that donor T cells undergo metabolic reprogramming after transplantation, switching from tricarboxylic cycle–mediated fatty acid β oxidation (FAO) and pyruvate oxidation to aerobic glycolysis. Importantly, pharmacological or genetic inhibition of glycolysis abrogated GVHD development. These data indicate targeting glycolysis may help to control GVHD.

Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantationHung D. Nguyen, Shilpak Chatterjee, Kelley M.K. Haarberg, Yongxia Wu, David Bastian, Jessica Heinrichs, Jianing Fu, Anusara Daenthanasanmak, Steven Schutt, Sharad Shrestha, Chen Liu, Honglin Wang, Hongbo Chi, Shikhar Mehrotra, and Xue-Zhong Yu http://jci.me/82587

Chimeric antigen receptor–bearing Tregs for transplantationRegulatory t cells (tregs) are critical in preventing autoimmunity and controlling responses to alloantigens in the setting of transplantation, and Treg-based therapy is emerging as a promising strategy to prevent or treat graft-versus-host disease (GVHD) and rejection. There is emerging evidence that disease-relevant, antigen-specific Tregs are more efficacious than polyclonal Tregs; however, the generation of alloantigen-specific Tregs relies on APC-mediated expansion and requires access to both donor and recipient tissues and multiple MHC mismatches. To circumvent these hurdles, Katherine MacDonald and colleagues engineered human Tregs bearing chimeric antigen receptors (CARs) specific for HLA-A2 (A2-CAR). In a murine model of hematopoietic stem cell transplantation, A2-CAR–expressing Tregs were superior to polyclonal Tregs in preventing GVHD caused by HLA-A2+ T cells. In the accompanying Commentary, Matthias Edinger discusses how these findings indicate that administration of CAR-Tregs may be a suitable approach for generating antigen-specific Tregs.

Alloantigen-specific regulatory T cells generated with a chimeric antigen receptorKatherine G. MacDonald, Romy E. Hoeppli, Qing Huang, Jana Gillies, Dan S. Luciani, Paul C. Orban, Raewyn Broady, and Megan K. Levings http://jci.me/82771

Related CommentaryDriving allotolerance: CAR-expressing Tregs for tolerance induction in organ and stem cell transplantationMatthias Edinger http://jci.me/86827

the role of macrophages in hiV infection is a topic of intense debate, and several recent studies have suggested that the presence of HIV in macrophages is the result of T cell engulfment rather than direct infection. To directly evaluate HIV replication in myeloid cells, Jenna Honeycutt and colleagues developed a humanized mouse model that is systemically reconstituted with human B cells and myeloid cells but is completely devoid of T cells (myeloid-only mice [MoM]). Using MoM, they demonstrated that myeloid cells sustained HIV replication in the absence of T cells. HIV-infected macrophages were distributed in every tissue analyzed, including the brain (see the accompanying image), where they have long been postulated to play a role in establishing HIV infection in the CNS. Moreover, infected macrophages could establish HIV infection in uninfected animals. These results demonstrate that macrophages are a target of HIV infection in vivo.

Macrophages sustain HIV replication in vivo independently of T cellsJenna B. Honeycutt, Angela Wahl, Caroline Baker, Rae Ann Spagnuolo, John Foster, Oksana Zakharova, Stephen Wietgrefe, Carolina Caro-Vegas, Victoria Madden, Garrett Sharpe, Ashley T. Haase, Joseph J. Eron, and J. Victor Garcia http://jci.me/84456

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JCI research | Editor’s picks

Murine models of vanishing white matter leukodystrophy

NOTCH signaling forms a more perfect union in bones

bone biology

neuroscience

Vanishing white matter (VWM) is a form of fatal leukodystrophy that is caused by mutations in eukaryotic translation initiation factor 2B (eIF2B). Stephanie Dooves, Marianna Bugiani, and colleagues developed murine models of VWM with mutations that cause severe disease in humans. Similar to humans, the mice had a highly variable phenotypic severity, and all of the strains showed impaired white matter astrocyte maturation (see the accompanying image) that was apparent prior to disease onset and increased in parallel with disease severity. The disease also affected non-forebrain astrocytes, which was not previously recognized in patients with VWM. Dooves, Bugiani, and colleagues found that VWM astrocytes secrete factors

that prevent oligodendrocyte maturation. These studies confirm that astrocytes are central to VWM pathogenesis.

Astrocytes are central in the pathomechanisms of vanishing white matterStephanie Dooves, Marianna Bugiani, Nienke L. Postma, Emiel Polder, Niels Land, Stephen T. Horan, Anne-Lieke F. van Deijk, Aleid van de Kreeke, Gerbren Jacobs, Caroline Vuong, Jan Klooster, Maarten Kamermans, Joke Wortel, Maarten Loos, Lisanne E. Wisse, Gert C. Scheper, Truus E.M. Abbink, Vivi M. Heine, and Marjo S. van der Knaap http://jci.me/83908

Approximately 10%–20% of fractures permanently fail to heal, a condition known as nonunion. Fracture repair appears to be achieved through both proliferation and differentiation of skeletal progenitors, but the factors governing these cells after a fracture are unknown. NOTCH signaling is required for the maintenance of bone marrow/stromal stem cells (BMSCs) during skeletal development. Cuicui Wang and colleagues examined the role of NOTCH in fracture union by examining healing of nonstabilized and stabilized fractures in mice with targeted deletion of the NOTCH signaling mediator RBPjk in BMSCs, maturing osteoblasts, and committed chondrocytes. They found that fracture nonunion only occurred in mice that lacked NOTCH signaling in BMSCs (see the accompanying image), ultimately resulting in BMSC depletion.

NOTCH signaling in skeletal progenitors is critical for fracture repairCuicui Wang, Jason A. Inzana, Anthony J. Mirando, Yinshi Ren, Zhaoyang Liu, Jie Shen, Regis J. O’Keefe, Hani A. Awad, and Matthew J. Hilton http://jci.me/80672

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JCI research | Editor’s picks

Shifting the balance in alternative splicing to rescue laminopathiesthe LMNA gene produces two alternatively spliced transcripts encoding the proteins lamin A and lamin C. Both proteins are produced in nearly equal amounts in most tissues and appear to play largely redundant roles in maintaining the nuclear lamina. Most disease-causing LMNA mutations affect both lamin A and lamin C; however, the most common LMNA mutations causing Hutchinson-Gilford progeria syndrome (HGPS) only affect lamin A synthesis, producing a truncated mutant form of lamin A (progerin). In this issue, John Lee and colleagues hypothesized that HGPS could be treated by shifting the balance of LMNA splicing toward lamin C to reduce the synthesis of progerin. They identified an antisense oligonucleotide (ASO) targeting exon 11 of LMNA that increased lamin C production at the expense of lamin A. Importantly, treatment of WT or HGPS mice with the ASO reduced lamin A and progerin expression, respectively. In the accompanying Commentary, Elizabeth McNally and Eugene Wyatt discuss how these findings suggest that strategies to alter LMNA splicing may be a promising treatment approach for lamin A–specific diseases.

Modulation of LMNA splicing as a strategy to treat prelamin A diseasesJohn M. Lee, Chika Nobumori, Yiping Tu, Catherine Choi, Shao H. Yang, Hea-Jin Jung, Timothy A. Vickers, Frank Rigo, C. Frank Bennett, Stephen G. Young, and Loren G. Fong http://jci.me/85908

Related CommentaryWelcome to the splice age: antisense oligonucleotide–mediated exon skipping gains wider applicabilityElizabeth M. McNally and Eugene J. Wyatt http://jci.me/86799

epigenetic-mediated cell fate specification is critical in development and stem cell–mediated tissue regeneration. Hervé Faralli and colleagues demonstrate that the histone demethylase UTX is required for satellite cell–mediated muscle regeneration. KO of Utx in female mice results in embryonic lethality; however, KO of Utx in male mice, which express a Y chromosome–encoded UTX paralog that does not have demethylase activity, survive. Faralli and colleagues generated mice with inducible, satellite cell–specific knockdown of UTX to investigate the role of UTX in muscle regeneration. Loss of UTX in satellite cells blocked myofiber regeneration (see the accompanying image). Moreover, regeneration was blocked by pharmacological inhibition of UTX demethylase activity or knock-in of an enzymatically dead mutant. Mechanistically, UTX was required for the terminal differentiation of satellite cells and the expression of a muscle gene expression program driven by histone demethylation. In the accompanying Commentary, Ling Liu and Thomas Rando discuss how these data identify a role for epigenetic regulation in myofiber regeneration.

UTX demethylase activity is required for satellite cell–mediated muscle regenerationHervé Faralli, Chaochen Wang, Kiran Nakka, Aissa Benyoucef, Soji Sebastian, Lenan Zhuang, Alphonse Chu, Carmen G. Palii, Chengyu Liu, Brendan Camellato, Marjorie Brand, Kai Ge, and F. Jeffrey Dilworth http://jci.me/83239

Related CommentaryUTX in muscle regeneration — the right dose and the right timeLing Liu and Thomas A. Rando http://jci.me/86798

muscle biologygenetics

Stem cell–mediated muscle regeneration requires UTX histone demethylase activity

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JCI research | Editor’s picks

Influenza-induced lung edema is mediated by macrophage/epithelial cell crosstalkinfluenza A virus (iAV) infection can cause lung injury and acute respiratory distress syndrome (ARDS) characterized by lung edema. Normally, alveolar epithelial cells (AECs) clear the excess fluid driven by the activity of the Na/K-ATPase; however, this mechanism appears to be impaired in ARDS. Christin Peteranderl and colleagues identified a paracrine communication network involving IAV-infected and uninfected AECs and alveolar macrophages, which drives decreased expression of the Na/K-ATPase, resulting in impaired alveolar fluid clearance. Mechanistic studies revealed that IAV infection induces an IFN-α/TRAIL signaling loop between AECs and macrophages that activates AMPK in AECs, triggering decreased plasma membrane expression of Na/K-ATPase. Importantly, antibody-mediated disruption of this signaling loop in mice improved the expression of Na/K-ATPase on AECs and reduced lung edema after IAV infection (see the accompanying image). In the accompanying Commentary, Rena Brauer and Peter Chen discuss how the paracrine network may be a suitable therapeutic target in lung edema.

pulmonology

Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infectionChristin Peteranderl, Luisa Morales-Nebreda, Balachandar Selvakumar, Emilia Lecuona, István Vadász, Rory E. Morty, Carole Schmoldt, Julia Bespalowa, Thorsten Wolff, Stephan Pleschka, Konstantin Mayer, Stefan Gattenloehner, Ludger Fink, Juergen Lohmeyer, Werner Seeger, Jacob I. Sznajder, Gökhan M. Mutlu, G.R. Scott Budinger, and Susanne Herold http://jci.me/83931

Related CommentaryInfluenza leaves a TRAIL to pulmonary edemaRena Brauer and Peter Chen http://jci.me/86802

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JCI research | Editor’s picks

Gastrokine-2 restrains inflammation to attenuate gastric tumorigenesis

oncology

Epigenetic drivers in meningioma-1–induced acute myeloid leukemiaMeningioma-1 (Mn1) is frequently overexpressed in acute myeloid leukemia (AML) and is associated with poor prognosis. Forced overexpres-sion of MN1 (MN1hi) in mice causes an aggressive myeloid leukemia that is dependent on a well-defined gene expression program, but the factors mediating this program are unknown. Simone Riedel, Jessica Haladyna, and colleagues demonstrate that two histone methyltransferases, MLL1 and DOT1L, control the gene expression program underlying MN1hi leukemia. Deletion of either Mll1 or Dot1l impaired MN1-mediated leukemogenesis and blocked expression of key leukemogenic genes. Moreover, Riedel, Haladyna, and colleagues determined that a subset of MN1hi primary patient leukemias coexpressing the MLL1 downstream target gene HOXA9 were sensitive to DOT1L inhibition, suggesting that DOT1L inhibition may be a suitable therapeutic strategy in this AML subtype.

MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemiaSimone S. Riedel, Jessica N. Haladyna, Matthew Bezzant, Brett Stevens, Daniel A. Pollyea, Amit U. Sinha, Scott A. Armstrong, Qi Wei, Roy M. Pollock, Scott R. Daigle, Craig T. Jordan, Patricia Ernst, Tobias Neff, and Kathrin M. Bernt http://jci.me/80825

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

Chronic inflammation due to Helicobacter pylori infection or other causes is a key risk factor in the development of gastric cancer (GC), but the mechanisms underlying this link are unclear. In this issue, Trevelyan Menheniott and colleagues analyzed gene expression in both human and murine GCs and found that loss of gastrokine-2 (GKN2) in the gastric mucosa was associated with tumor progression. Targeted deletion of Gkn2 in mice caused mucosal defects and potentiated tumorigenesis of the gastric corpus in a cytokine-driven murine GC model (gp130F/F). Conversely, overexpression of human gastrokines attenuated tumorigenesis in this model (see the accompanying image). Loss of Gkn2 in H. pylori–infected mice accelerated progression of atrophic gastritis and mucosal metaplasia that was driven by heightened innate immune responses and impaired myeloid-derived suppressor cell responses, promoting inflammation. These data establish gastrokines as critical suppressors of inflammation-driven gastric tumors.

Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progressionTrevelyan R. Menheniott, Louise O’Connor, Yok Teng Chionh, Jan Däbritz, Michelle Scurr, Benjamin N. Rollo, Garrett Z. Ng, Shelley Jacobs, Angelique Catubig, Bayzar Kurklu, Stephen Mercer, Toshinari Minamoto, David E. Ong, Richard L. Ferrero, James G. Fox, Timothy C. Wang, Philip Sutton, Louise M. Judd, and Andrew S. Giraud http://jci.me/82655

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Targeting the prion-like protein doppel to block tumor angiogenesis

Cancer cells exploit neural repair pathways to enhance invasion

JCI research | Editor’s picks

oncology

Antiangiogenic therapies targeting VeGF and its receptors are used to treat a variety of solid tumors; however, these drugs target both cancerous and healthy tissues, making a tumor-specific therapy desirable. Taslim Al-Hilal and colleagues report that the prion-like protein doppel is expressed in tumor-associated vascular endothelial cells (ECs), but not in normal endothelium (see the accompanying image). In a murine s.c. tumor xenograft model, doppel overexpression in ECs enhanced tumor vascularization, while doppel inhibition reduced tumor vascularization by promoting VEGFR2 internalization and degradation in tumor-associated ECs. Administration of an orally active glycosaminoglycan,

LHbisD4, which specifically binds with doppel and concentrates over the tumor site, replicated doppel inhibition. These results indicate that doppel is a selective therapeutic target for blocking tumor angiogenesis.

Targeting prion-like protein doppel selectively suppresses tumor angiogenesisTaslim A. Al-Hilal, Seung Woo Chung, Jeong Uk Choi, Farzana Alam, Jooho Park, Seong Who Kim, Sang Yoon Kim, Fakhrul Ahsan, In-San Kim, and Youngro Byun http://jci.me/83427

Perineural invasion commonly occurs with a variety of malignancies and is associated with increased risk of local recurrence and poor prognosis, but the mechanisms by which nerves contribute to cancer progression are poorly understood. Using murine and human tumor specimens, Sylvie Deborde and colleagues demonstrated that a subpopulation of Schwann cells associates with cancer cells (see the accompanying image). Coculture studies revealed

that Schwann cells recruit cancer cells and induce the cancer cells to form protrusions directed toward the Schwann cells via neural cell adhesion molecule 1 (NCAM1). This interaction allows the Schwann cells to insinuate themselves between the cancer cells, dispersing them and promoting invasion. In the accompanying Commentary, Salma Azam and Chad Pecot discuss how these findings define a mecha-nism underlying perineural invasion.

Schwann cells induce cancer cell dispersion and invasionSylvie Deborde, Tatiana Omelchenko, Anna Lyubchik, Yi Zhou, Shizhi He, William F. McNamara, Natalya Chernichenko, Sei-Young Lee, Fernando Barajas, Chun-Hao Chen, Richard L. Bakst, Efsevia Vakiani, Shuangba He, Alan Hall, and Richard J. Wong http://jci.me/82658

Related CommentaryCancer’s got nerve: Schwann cells drive perineural invasionSalma H. Azam and Chad V. Pecot http://jci.me/86801

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JCI research | Editor’s picks

immunology

DAB2 tips the balance in macrophage polarization

Estrogen-induced repression of AIRE may underlie sexual dimorphism in autoimmunityFemales are more susceptible to autoimmune diseases than males. Nadine Dragin and colleagues identified sex differences in thymic expression of tissue-specific antigens controlled by the autoimmune regulator (AIRE), which directly regulates the generation of autoreactive immune cells. Therefore, they tested the hypothesis that AIRE levels are linked to the sexual dimorphism of autoimmune disease susceptibility. They found that after puberty, both human and murine females expressed less AIRE in thymic epithelial cells than did males. Moreover, AIRE expression was related to sex hormones, as both male castration and estrogen administration decreased expression of AIRE in the thymus. Mechanistically, estrogen increased CpG methylation within the AIRE promoter in human thymic epithelial cells (see the accompanying image). In the related Commentary, Pearl Bakhru and Maureen Su

discuss how these studies indicate that higher estrogen levels in females induce epigenetic changes that reduce AIRE expression and increase susceptibility to autoimmune diseases.

Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseasesNadine Dragin, Jacky Bismuth, Géraldine Cizeron-Clairac, Maria Grazia Biferi, Claire Berthault, Alain Serraf, Rémi Nottin, David Klatzmann, Ana Cumano, Martine Barkats, Rozen Le Panse, and Sonia Berrih-Aknin http://jci.me/81894

Related CommentaryEstrogen turns down “the AIRE”Pearl Bakhru and Maureen A. Su http://jci.me/86800

Macrophages change their phenotype and function in response to environmental cues generated during acute and chronic tissue injury. In order to identify regulators of macrophage phenotypic polarization, Samantha Adamson, Rachael Griffiths, and colleagues compared gene expression patterns of in vitro polarized macro-phages. They found that disabled homolog 2 (DAB2) was upregulated in M2 macrophages and downregulated in M1 macrophages. Mice with myeloid-specific deletion of Dab2 showed enhanced

inflammatory responses to LPS, with increased inflammatory gene expression and macrophage activation. Further, chronic high-fat feeding of these mice resulted in increased adipose tissue inflammation, M1 polarization of adipose tissue–resident macrophages, and insulin resistance. Mechanistically, DAB2 attenuates inflammatory NF-κB signaling through interactions with TNF receptor–associated factor 6 (TRAF6). These findings suggest that DAB2 may be a suitable therapeutic target in inflammatory disorders.

Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammationSamantha E. Adamson, Rachael Griffiths, Radim Moravec, Subramanian Senthivinayagam, Garren Montgomery, Wenshu Chen, Jenny Han, Poonam R. Sharma, Garrett R. Mullins, Stacey A. Gorski, Jonathan A. Cooper, Alexandra Kadl, Kyle Enfield, Thomas J. Braciale, Thurl E. Harris, and Norbert Leitinger http://jci.me/79590

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JCI Review Series

Extracellular vesicles

Cell-to-cell communication is an essential component in multicellular organisms, allowing for rapid, coordinat-ed responses to changes within the environment. Clas-sical signaling mediators include direct cell-cell contact as well as secreted factors, such as cytokines, metabo-lites, and hormones. In the past decade, extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as important mediators of intercellular communication. EVs are double- membrane vesicles containing cargoes of multiple proteins, lipids, and nucleic acids, which are derived from their cells of origin, and EV cargoes can change depending on the status of their originating cells. Importantly, EVs are found in all body fluids and can carry their cargoes to distant sites within the body as well as neighboring cells. Reviews in this series discuss the role of EV-mediated signaling in physiological and pathophysiological conditions, including infection, host immune responses, and cancer. Additionally, these Reviews discuss the potential clinical use of EVs as therapeutics and diagnostic biomarkers.

Extracellular vesicles: masters of intercellular communication and potential clinical interventionsJonathan M. Pitt, Guido Kroemer, and Laurence Zitvogel

http://jci.me/87316

Dr. Laurence Zitvogel is the Research Director at Institut National de la Santé et Recherche Médicale and a Co-Director of a Center of Clinical Investigations at Institut Gustave Roussy, Villejuif, France. She graduated in 1992 with a degree in medical oncology from the School of Medicine of the University of Paris. She began her scientific career at the University of Pittsburgh, work-ing under Michael Lotze. Her expertise is mainly the biology of dendritic and innate effector cells, and their relevance during tumor development and cancer immunotherapy. Dr. Zitvogel currently investigates the immunogenicity of cell death with drugs of the oncological armamentarium as well as dendritic cell–derived autologous exosome vaccines.

Getting the message: extracellular vesicles in health and disease

Series Editor: laurence Zitvogel

Prostasomes as a source of diagnostic biomarkers for prostate cancerCarla Zijlstra and Willem Stoorvogel http://jci.me/81128

Extracellular vesicle isolation and characterization: toward clinical applicationRong Xu, David W. Greening, Hong-Jian Zhu, Nobuhiro Takahashi, and Richard J. Simpson http://jci.me/81129

Versatile roles of extracellular vesicles in cancerNobuyoshi Kosaka, Yusuke Yoshioka, Yu Fujita, and Takahiro Ochiya http://jci.me/81130

Regulation of chronic inflammatory and immune processes by extracellular vesiclesPaul D. Robbins, Akaitz Dorronsoro, and Cori N. Booker http://jci.me/81131

Extracellular vesicles and infectious diseases: new complexity to an old storyJeffrey S. Schorey and Clifford V. Harding http://jci.me/81132

Exosomes in stroke pathogenesis and therapyZheng Gang Zhang and Michael Chopp http://jci.me/81133

Extracellular vesicles and intercellular communication within the nervous systemValentina Zappulli, Kristina Pagh Friis, Zachary Fitzpatrick, Casey A. Maguire, and Xandra O. Breakefield http://jci.me/81134

The biology and function of exosomes in cancerRaghu Kalluri http://jci.me/81135

Exosomes and tumor-mediated immune suppressionTheresa L. Whiteside http://jci.me/81136

Dendritic cell–derived exosomes for cancer therapyJonathan M. Pitt, Fabrice André, Sebastian Amigorena, Jean-Charles Soria, Alexander Eggermont, Guido Kroemer, and Laurence Zitvogel http://jci.me/81137

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Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse modelJenny L. Sones, Jeeyeon Cha, Ashley K. Woods, Amanda Bartos, Christa Y. Heyward, Heinrich E. Lob, Catherine E. Isroff, Scott D. Butler, Stephanie E. Shapiro, Sudhansu K. Dey, and Robin L. Davisson http://jci.me/75351

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in miceAlexandra Kuznetsova, Yue Yu, Jennifer Hollister-Lock, Lynn Opare-Addo, Aldo Rozzo, Marianna Sadagurski, Lisa Norquay, Jessica E. Reed, Ilham El Khattabi, Susan Bonner-Weir, Gordon C. Weir, Arun Sharma, and Morris F. White http://jci.me/80749

Maturational characteristics of HIV-specific antibodies in viremic individuals

Eric Meffre, Aaron Louie, Jason Bannock, Leo J.Y. Kim, Jason Ho, Cody C. Frear, Lela Kardava, Wei Wang, Clarisa M. Buckner, Yimeng Wang, Olivia R. Fankuchen, Kathleen R. Gittens, Tae-Wook Chun, Yuxing Li, Anthony S. Fauci, and Susan Moir http://jci.me/84610

Identification of human plasma cells with a lamprey monoclonal antibodyCuiling Yu, Yanling Liu, Justin Tze Ho Chan, Jiefei Tong, Zhihua Li, Mengyao Shi, Dariush Davani, Marion Parsons, Srijit Khan, Wei Zhan, Shuya Kyu, Eyal Grunebaum, Paolo Campisi, Evan J. Propst, David L. Jaye, Suzanne Trudel, Michael F. Moran, Mario Ostrowski, Brantley R. Herrin, F. Eun-Hyung Lee, Ignacio Sanz, Max D. Cooper, and Götz R.A. Ehrhardt http://jci.me/84738

Innate immune reconstitution with suppression of HIV-1Eileen P. Scully, Ainsley Lockhart, Wilfredo Garcia-Beltran, Christine D. Palmer, Chelsey Musante, Eric Rosenberg, Todd M. Allen, J. Judy Chang, Ronald J. Bosch, and Marcus Altfeld http://jci.me/85433

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysisHani Bagheri, Chansonette Badduke, Ying Qiao, Rita Colnaghi, Iga Abramowicz, Diana Alcantara, Christopher Dunham, Jiadi Wen, Robert S. Wildin, Malgorzata J.M. Nowaczyk, Jennifer Eichmeyer, Anna Lehman, Bruno Maranda, Sally Martell, Xianghong Shan, Suzanne M.E. Lewis, Mark O’Driscoll, Cheryl Y. Gregory-Evans, and Evica Rajcan-Separovic http://jci.me/85461

The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemiaKatherine A. Minson, Catherine C. Smith, Deborah DeRyckere, Clara Libbrecht, Alisa B. Lee-Sherick, Madeline G. Huey, Elisabeth A. Lasater, Gregory D. Kirkpatrick, Michael A. Stashko, Weihe Zhang, Craig T. Jordan, Dmitri Kireev, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Neil P. Shah, and Douglas K. Graham http://jci.me/85630

Claudin-low bladder tumors are immune infiltrated and actively immune suppressedJordan Kardos, Shengjie Chai, Lisle E. Mose, Sara R. Selitsky, Bhavani Krishnan, Ryoichi Saito, Michael D. Iglesia, Matthew I. Milowsky, Joel S. Parker, William Y. Kim, and Benjamin G. Vincent http://jci.me/85902

JCI Insight is a new peer-reviewed journal dedicated to biomedical research, ranging from preclinical to clinical studies.

Published March 17, 2016

More information: http://jci.me/insinf or editors@insight.jci.org

Insulin-producing cells

Zebrafish rel deficiency