MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium-induced colitis.
Myeloid differentiation factor (MyD)88, an adaptor protein shared by the Toll-interleukin 1 receptor superfamily, plays a critical role in host defence during many systemic bacterial infections by inducing protective inflammatory responses that limit bacterial growth. However, the role of innate responses during gastrointestinal (GI) infections is less clear, in part because the GI tract is tolerant to commensal antigens. The current study investigated the role of MyD88 following infection by the murine bacterial pathogen, Citrobacter rodentium. MyD88-deficient mice suffered a lethal colitis coincident with colonic mucosal ulcerations and bleeding. Their susceptibility was associated with an overwhelming bacterial burden and selectively impaired immune responses in colonic tissues, which included delayed inflammatory cell recruitment, reduced iNOS and abrogated production of TNF-alpha and IL-6 from MyD88-deficient macrophages and colons cultured ex vivo. Immunostaining for Ki67 and BrDU revealed that MyD88 signalling mediated epithelial hyper-proliferation in response to C. rodentium infection. Thus, MyD88-deficient mice could not promote epithelial cell turnover and repair, leading to deep bacterial invasion of colonic crypts, intestinal barrier dysfunction and, ultimately, widespread mucosal ulcerations. In conclusion, MyD88 signalling within the GI tract plays a critical role in mediating host defence against an enteric bacterial pathogen, by controlling bacterial numbers and promoting intestinal epithelial homeostasis.
Gibson
D L
DL
Division of Gastroenterology, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Ma
C
C
Bergstrom
K S B
KS
Huang
J T
JT
Man
C
C
Vallance
B A
BA
D000818:Animals; D001853:Bone Marrow / Q000382:microbiology; D044082:Citrobacter rodentium / Q000276:immunology*; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000737:chemistry / Q000382:microbiology / Q000473:pathology; D015169:Colony Count, Microbial; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000382:microbiology*; D015850:Interleukin-6 / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D009924:Organ Culture Techniques; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015850:Interleukin-6; D019394:Ki-67 Antigen; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse