Tu173 - MyD88 in Stromal Cells Regulates Antimicrobial Defenses in Intestinal Macrophages in Early Stage of IBD

Christina McAninch – Penn State College of Medicine; Steven McAninch – Penn State College of Medicine; Don Powell, MD – The University of Texas Medical Branch; Pinchuk Iryna, PhD – Penn State College of Medicine

Abstract Text: The role of fibroblasts in the regulation of macrophage antimicrobial defense in the gut remains unknown. MyD88 is suggested to shape fibroblast responses in the intestinal microenvironment. We examined the role of fibroblast-intrinsic MyD88 signaling in regulation of antimicrobial activity in macrophages. Mice lacking MyD88 within fibroblasts showed a decrease in the activity of antimicrobial defense pathways in the colon, accumulation of immature Arginase 1+ macrophages with low production of antimicrobial peptide cathelicidin, development of dysbiosis, and aggravation of DSS-induced colitis. Priming of bone marrow-derived monocytes with colonic fibroblasts lacking MyD88 resulted in generation of macrophages with low production of antimicrobial molecules and decreased bactericidal function. The production of IL-6 and CCL2 downstream of MyD88 was critically involved in fibroblast-mediated regulation of macrophage antimicrobial function. Thus, fibroblast-intrinsic MyD88 signaling contributes to colonic homeostasis by regulating macrophage antimicrobial defense, and its disruption may predispose animals for the development of intestinal inflammation.