title: Epithelial cell-specific MyD88 signaling mediates ischemia/reperfusion-induced intestinal injury independent of microbial status.
abstract: The Toll-like receptor/MyD88 signaling pathway has been shown to mediate protective functions during intestinal exposure to various noxious events. The goal of this study was to define the role of bacteria and MyD88 signaling in intestinal response to damage using an ischemia-reperfusion (I/R)-induced injury model. We showed that conventionalized mice displayed a better outcome to I/R-induced injury than germ-free mice (3.8 ± 1.98 vs. 11.8 ± 1.83, P < 0.05). However, mice with intestinal epithelial cell (IEC)-specific deletion of Myd88 (Myd88) were protected from I/R-induced injury compared with Myd88 control mice. Myd88 mice also displayed a significantly reduced bacterial translocation (∼85%) into lymph nodes compared with Myd88 mice. Expression of ccl2 and cxcl1 mRNA was significantly reduced (85% and 62%, respectively) in intestinal tissue of Myd88 mice compared with Myd88 mice, which associated with a reduced number of myeloperoxidase-positive cells in intestinal tissues of I/R-exposed Myd88 mice. Immunohistochemistry analysis showed a reduced IgA deposition and complement staining in ischemic tissue of Myd88 mice compared with Myd88 mice. These findings suggest that I/R-induced intestinal injury involves IEC-derived MyD88 signaling leading to increased IgA deposition/degradation, and complement activation in conjunction with an influx of neutrophils mediated by chemokine production.
authors.affiliation: *Departments of Medicine, Microbiology and Immunology, and Pharmacology, University of North Carolina, Chapel Hill, North Carolina; and †Department of Medicine and Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida.
authors.forename: Marcus
authors.initials: M
authors.lastname: Mühlbauer
authors.forename: Ernesto
authors.initials: E
authors.lastname: Perez-Chanona
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
mesh_terms: D000818:Animals; D001419:Bacteria / Q000472:pathogenicity*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007422:Intestines / Q000293:injuries* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger