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

Cell Rep. 2019 Feb 5;26(6):1614-1626.e5. doi: 10.1016/j.celrep.2019.01.054.

Abstract

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.

Keywords: Citrobacter rodentium; IL-22; colitis; infection; inflammation; innate immunity; innate lymphoid cells; leukocyte adhesion deficiency; macrophages; β2-integrins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD18 Antigens / deficiency
  • CD18 Antigens / genetics*
  • CD18 Antigens / immunology
  • Citrobacter rodentium / immunology
  • Citrobacter rodentium / pathogenicity*
  • Colitis / genetics*
  • Colitis / immunology
  • Colitis / microbiology
  • Colitis / mortality
  • Enterobacteriaceae Infections / genetics*
  • Enterobacteriaceae Infections / immunology
  • Enterobacteriaceae Infections / microbiology
  • Enterobacteriaceae Infections / mortality
  • Female
  • Gene Expression Regulation / immunology
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Interleukin-22
  • Interleukins / genetics*
  • Interleukins / immunology
  • Intestines / immunology
  • Intestines / microbiology
  • Intestines / pathology
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Macrophages / pathology
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Neuropeptides / genetics
  • Neuropeptides / immunology
  • Neutrophil Infiltration
  • Neutrophils / immunology
  • Neutrophils / microbiology
  • Neutrophils / pathology
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Survival Analysis
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / immunology

Substances

  • CD18 Antigens
  • IL1B protein, mouse
  • Il17a protein, mouse
  • Inflammasomes
  • Interleukin-17
  • Interleukin-1beta
  • Interleukins
  • Lad1 protein, mouse
  • Membrane Glycoproteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neuropeptides
  • Nlrp3 protein, mouse
  • Rac1 protein, mouse
  • Reactive Oxygen Species
  • rac1 GTP-Binding Protein