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Horwitz, Bruce

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Horwitz

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Bruce

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Horwitz, Bruce

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2013 - 20182

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Author's Publications: search.filters.isAuthorOfPublication.e5b29654-d683-4f41-a662-d1b46b150edd

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    WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis
    (Nature Publishing Group UK, 2018) Biswas, Amlan; Shouval, Dror S.; Griffith, Alexandra; Goettel, Jeremy; Field, Michael; Kang, Yu Hui; Konnikova, Liza; Janssen, Erin; Redhu, Naresh; Thrasher, Adrian J.; Chatila, Talal; Kuchroo, Vijay; Geha, Raif; Notarangelo, Luigi D.; Pai, Sung-Yun; Horwitz, Bruce; Snapper, Scott
    Mutations in Wiskott–Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. The generation and function of anti-inflammatory macrophages are defective in both human and mice in the absence of WASP. Expression of WASP specifically in macrophages, but not in dendritic cells, is critical for regulation of colitis development. Importantly, transfer of WT anti-inflammatory macrophages prevents the development of colitis. DOCK8-deficient macrophages phenocopy the altered macrophage properties associated with WASP deficiency. Mechanistically, we show that both WASP and DOCK8 regulates macrophage function by modulating IL-10-dependent STAT3 phosphorylation. Overall, our study indicates that anti-inflammatory macrophage function and mucosal immune tolerance require both WASP and DOCK8, and that IL-10 signalling modulates a WASP-DOCK8 complex.
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    Pathogenic Intestinal Bacteria Enhance Prostate Cancer Development via Systemic Activation of Immune Cells in Mice
    (Public Library of Science, 2013) Poutahidis, Theofilos; Cappelle, Kelsey; Levkovich, Tatiana; Lee, Chung-Wei; Doulberis, Michael; Ge, Zhongming; Fox, James G.; Horwitz, Bruce; Erdman, Susan E.
    A role for microbes has been suspected in prostate cancer but difficult to confirm in human patients. We show here that a gastrointestinal (GI) tract bacterial infection is sufficient to enhance prostate intraepithelial neoplasia (PIN) and microinvasive carcinoma in a mouse model. We found that animals with a genetic predilection for dysregulation of wnt signaling, ApcMin/+ mutant mice, were significantly susceptible to prostate cancer in an inflammation-dependent manner following infection with Helicobacter hepaticus. Further, early neoplasia observed in infected ApcMin/+ mice was transmissible to uninfected mice by intraperitoneal injection of mesenteric lymph node (MLN) cells alone from H. hepaticus-infected mutant mice. Transmissibility of neoplasia was preventable by prior neutralization of inflammation using anti-TNF-α antibody in infected MLN donor mice. Taken together, these data confirm that systemic inflammation triggered by GI tract bacteria plays a pivotal role in tumorigenesis of the prostate gland.