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

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 K. Kuchroo, Raif S Geha, Luigi D. Notarangelo, Sung-Yun Pai, Bruce H. Horwitz and Scott B. Snapper ()
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Amlan Biswas: Boston Children’s Hospital
Dror S. Shouval: Boston Children’s Hospital
Alexandra Griffith: Boston Children’s Hospital
Jeremy A. Goettel: Boston Children’s Hospital
Michael Field: Boston Children’s Hospital
Yu Hui Kang: Boston Children’s Hospital
Liza Konnikova: Boston Children’s Hospital
Erin Janssen: Harvard Medical School
Naresh Singh Redhu: Boston Children’s Hospital
Adrian J. Thrasher: University College London
Talal Chatila: Harvard Medical School
Vijay K. Kuchroo: Harvard Medical School and Brigham and Women’s Hospital
Raif S Geha: Harvard Medical School
Luigi D. Notarangelo: National Institutes of Health
Sung-Yun Pai: Boston Children’s Hospital Boston
Bruce H. Horwitz: Harvard Medical School
Scott B. Snapper: Boston Children’s Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03670-6

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