Irgm1-deficiency leads to myeloid dysfunction in colon lamina propria and susceptibility to the intestinal pathogen Citrobacter rodentium

PLoS Pathog. 2020 May 26;16(5):e1008553. doi: 10.1371/journal.ppat.1008553. eCollection 2020 May.

Abstract

IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity. IRGM dysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.

Publication types

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

MeSH terms

  • Animals
  • Citrobacter rodentium / immunology*
  • Colon / immunology*
  • Colon / microbiology
  • Colon / pathology
  • Enterobacteriaceae Infections / genetics
  • Enterobacteriaceae Infections / immunology*
  • Enterobacteriaceae Infections / pathology
  • GTP-Binding Proteins / deficiency*
  • GTP-Binding Proteins / immunology
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / immunology*
  • Inflammatory Bowel Diseases / microbiology
  • Inflammatory Bowel Diseases / pathology
  • Mice
  • Mice, Knockout
  • Monocytes / immunology*
  • Monocytes / microbiology
  • Monocytes / pathology
  • Mucous Membrane / immunology
  • Mucous Membrane / microbiology
  • Mucous Membrane / pathology

Substances

  • Ifi1 protein, mouse
  • GTP-Binding Proteins