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

Amlan Biswas,Bruce H Horwitz,Naresh Singh Redhu,Yu Hui Kang,Dror S Shouval,Liza Konnikova,Scott B Snapper,Jeremy A Goettel,Vijay K Kuchroo,Michael Field,Alexandra Griffith,Erin Janssen,Talal Chatila,Raif S Geha,Luigi D Notarangelo,Adrian J Thrasher,Sung-Yun Pai

doi:10.1038/s41467-018-03670-6

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.

Highlights

Mutations in Wiskott–Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis
To examine whether WASP regulates lamina propria (LP) macrophage differentiation and function, and to minimize any effect that inflammation may have on skewing of macrophage differentiation, we compared the phenotype of colonic macrophages from pre-colitic 5-week-old Was−/− and wild-type (WT) mice
To further characterize functionally LP macrophages, we evaluated the expression of pro- and anti-inflammatory genes expression in sorted P3 + P4 macrophages isolated from 5-week-old Was−/− and WT mice

Summary

Introduction

Mutations in Wiskott–Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. We show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. Expression of WASP in macrophages, but not in dendritic cells, is critical for regulation of colitis development. 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. Was−/−Rag2−/− mice rapidly lose weight and develop severe colitis after transfer of unfractionated WT CD4+ T cells, whereas Rag2−/− mice that express WASP do not develop colitis[12] Together, these studies suggest that WASP function within an innate immune cell is necessary to avert intestinal inflammation. We show that IL-10 modulates a WASP:DOCK8-signalling complex These data demonstrate that WASP regulates intestinal homeostasis through modulation of anti-inflammatory macrophages

Methods

Results

Conclusion