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WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis

Author

Listed:
  • Amlan Biswas

    (Boston Children’s Hospital
    Harvard Medical School
    300 Longwood Avenue)

  • Dror S. Shouval

    (Boston Children’s Hospital
    300 Longwood Avenue
    Edmond and Lily Safra Children’s Hospital, Sheba Medical Center
    Tel Aviv University)

  • Alexandra Griffith

    (Boston Children’s Hospital
    300 Longwood Avenue)

  • Jeremy A. Goettel

    (Boston Children’s Hospital
    Harvard Medical School
    300 Longwood Avenue)

  • Michael Field

    (Boston Children’s Hospital
    300 Longwood Avenue)

  • Yu Hui Kang

    (Boston Children’s Hospital
    Harvard Medical School
    300 Longwood Avenue)

  • Liza Konnikova

    (Boston Children’s Hospital
    Harvard Medical School
    300 Longwood Avenue)

  • Erin Janssen

    (Harvard Medical School
    Boston Children’s Hospital)

  • Naresh Singh Redhu

    (Boston Children’s Hospital
    Harvard Medical School
    300 Longwood Avenue)

  • Adrian J. Thrasher

    (University College London)

  • Talal Chatila

    (Harvard Medical School
    Boston Children’s Hospital)

  • Vijay K. Kuchroo

    (Harvard Medical School and Brigham and Women’s Hospital)

  • Raif S Geha

    (Harvard Medical School
    Boston Children’s Hospital)

  • Luigi D. Notarangelo

    (National Institutes of Health)

  • Sung-Yun Pai

    (Boston Children’s Hospital Boston)

  • Bruce H. Horwitz

    (Harvard Medical School
    300 Longwood Avenue
    Brigham and Women’s Hospital
    Boston Children’s Hospital, Boston)

  • Scott B. Snapper

    (Boston Children’s Hospital
    300 Longwood Avenue
    Department of Medicine, Harvard Medical School)

Abstract

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.

Suggested Citation

  • Amlan Biswas & Dror S. Shouval & Alexandra Griffith & Jeremy A. Goettel & Michael Field & Yu Hui Kang & Liza Konnikova & Erin Janssen & Naresh Singh Redhu & Adrian J. Thrasher & Talal Chatila & Vijay , 2018. "WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03670-6
    DOI: 10.1038/s41467-018-03670-6
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