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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Taylor, GA; Huang, H-I; Fee, BE; Youssef, N; Jewell, ML; Cantillana, V; Schoenborn, AA; Rogala, AR; Buckley, AF; Feng, CG; Vallance, BA; Gulati, AS; Hammer, GE

Published Date

  • May 2020

Published In

Volume / Issue

  • 16 / 5

Start / End Page

  • e1008553 -

PubMed ID

  • 32453761

Pubmed Central ID

  • 32453761

Electronic International Standard Serial Number (EISSN)

  • 1553-7374

Digital Object Identifier (DOI)

  • 10.1371/journal.ppat.1008553

Language

  • eng

Conference Location

  • United States