Macrophage β2-Integrins Regulate IL-22 by ILC3s and Protect from Lethal Citrobacter rodentium-Induced Colitis

• Main Authors: Baomei Wang, Jong-Hyung Lim, Tetsuhiro Kajikawa, Xiaofei Li, Bruce A. Vallance, Niki M. Moutsopoulos, Triantafyllos Chavakis, George Hajishengallis
• Format: Article
• Language: English
• Published: Elsevier 2019-02-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112471930083X

Summary: β2-integrins promote neutrophil recruitment to infected tissues and are crucial for host defense. Neutrophil recruitment is defective in leukocyte adhesion deficiency type-1 (LAD1), a condition caused by mutations in the CD18 (β2-integrin) gene. Using a model of Citrobacter rodentium (CR)-induced colitis, we show that CD18−/− mice display increased intestinal damage and systemic bacterial burden, compared to littermate controls, ultimately succumbing to infection. This phenotype is not attributed to defective neutrophil recruitment, as it is shared by CXCR2−/− mice that survive CR infection. CR-infected CD18−/− mice feature prominent upregulation of IL-17 and downregulation of IL-22. Exogenous IL-22 administration, but not endogenous IL-17 neutralization, protects CD18−/− mice from lethal colitis. β2-integrin expression on macrophages is mechanistically linked to Rac1/ROS-mediated induction of noncanonical-NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome-dependent IL-1β production, which promotes ILC3-derived IL-22. Therefore, β2-integrins are required for protective IL-1β-dependent IL-22 responses in colitis, and the identified mechanism may underlie the association of human LAD1 with colitis. : Wang et al. show that β2-integrin expression on intestinal macrophages is required for Rac1/ROS-mediated induction of noncanonical-NLRP3 inflammasome-dependent IL-1β production, which in turn promotes ILC3-derived IL-22. Reduced production of IL-22 due to β2-integrin deficiency in mice causes lethal C. rodentium colitis. Keywords: Citrobacter rodentium, infection, colitis, β2-integrins, leukocyte adhesion deficiency, macrophages, innate lymphoid cells, IL-22, innate immunity, inflammation