Differential roles for Irgm1 in myeloid cells for immune resistance to pathogenic bacteria.

Abstract

IRGM proteins are associated with increased susceptibility to Crohn's disease, mycobacterial infections, sepsis, and other inflammatory diseases, but the cells in which they function in vivo have not been delineated. To address this, mice with conditional deletions of Irgm1 were created and challenged with model pathogens. Irgm1fl/flLyz2-Cre+ mice (a myeloid deletion) displayed marked susceptibility to infections with Salmonella typhimurium, Listeria monocytogenes, and Toxoplasma gondii, paralleling those of global Irgm1-/- mice. However, infections of Irgm1fl/flLyz2-Cre+ mice with Citrobacter rodentium showed no increase in susceptibility, contrasting with marked increases in Irgm1fl/flVav-Cre+ mice (a hematopoietic deletion). Macrophages from Irgm1fl/flLyz2-Cre+ mice displayed pathologies present in macrophages from global Irgm1-/- mice, validating the conditional deletion in myeloid cells. These results suggest that Irgm1 functioning in myeloid cells is critical for immune resistance to intracellular pathogens, while Irgm1 functioning in additional hematopoietic population(s) is required for resistance to extracellular pathogens in the intestinal lumen.