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

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

Irgm1 regulates metabolism and function in T cell subsets

“…In the current work, we also found that 2DG reversed the decreased T cell viability that was found to accompany Irgm1 -deficiency in T cells. Thus, our findings add to and reinforce a growing hypothetical structure suggesting that loss of Irgm1 triggers at least two related pathways: (1) altered mitochondrial metabolism drives cytokine production and apoptotic cell death 15 , 27 as demonstrated here, and (2) decreases in clearance of damaged mitochondria prompt mitochondrial DNA engagement of the TLR7 and/ or cGAS/STING pathways driving further cytokine production as shown recently elsewhere 16 , 19 .…”

“…Our data demonstrate that Th1 CD4 T cells lacking Irgm1 have decreased cell survival as well as deficient function of existing cells, which in combination may well lead to failure to suppress populations of inflammatory enteric bacteria. Along those lines, our recent work has indicated that Irgm1 -deficient mice are unable to control replication and spread of the enteric bacterium and IBD model, Citrobacter rodentium 27 . Our current results also demonstrate that Treg cells lacking Irgm1 have impaired regulatory function, which likely also contributes to inefficient suppression of intestinal inflammatory mechanisms.…”

“…One study found that Irgm1 regulates homeostasis of CD3 + T cells during chronic mycobacterial infection by driving expansion of bone marrow progenitor cells, likely as a consequence of the ability of Irgm1 to regulate autophagy 24 – 26 . A more recent study found a decrease in Th1 cells in the lamina propria of Irgm1 −/− mice that were infected with the enteric bacterium Citrobacter rodentium , though the underlying mechanism was not addressed, and it was not clear whether that was a primary or secondary consequence of Irgm1-deficiency 27 . Thus, there is a need to understand how IRGM/Irgm1 may regulate the development, homeostasis, and function of mature T cell subsets.…”

Immunity-related GTPase IRGM at the intersection of autophagy, inflammation, and tumorigenesis

“…Considering that H. pylori induces IRGM downregulation in a strain-dependant manner, IRGM polymorphisms and microbial suppression act synergistically to prevent xenophagic clearance [49]. The deletion or knockdown of the murine ortholog Irgm1 results in increased susceptibility to both intracellular and extracellular bacteria, including Citrobacter rodentium [50], S. typhimurium [9], Mycobacterium tuberculosis [12], Listeria monocytogenes [51], and C. trachomatis [52]. Numerous mechanisms for increased susceptibility in murine Irgm1 −/− models have been proposed: failure of monocyte maturation upon lamina propia infiltration and apoptosis [50], abolishment of macrophage movement and adhesion [9], and loss of intracellular bacterial restriction mechanisms [52].…”

“…The deletion or knockdown of the murine ortholog Irgm1 results in increased susceptibility to both intracellular and extracellular bacteria, including Citrobacter rodentium [50], S. typhimurium [9], Mycobacterium tuberculosis [12], Listeria monocytogenes [51], and C. trachomatis [52]. Numerous mechanisms for increased susceptibility in murine Irgm1 −/− models have been proposed: failure of monocyte maturation upon lamina propia infiltration and apoptosis [50], abolishment of macrophage movement and adhesion [9], and loss of intracellular bacterial restriction mechanisms [52]. In vitro models using M. leprae and M. tuberculosis corroborate murine models, identifying increased IRGM expression upon infection [12,53].…”