Umang Jain1, Craig A Midgen, Wilhelm J Schwaeble, Cordula M Stover, Andrew W Stadnyk. 1. Departments of *Microbiology and Immunology, and †Pathology, Dalhousie University, Halifax, NS, Canada; ‡Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; and §Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.
Abstract
BACKGROUND: Interleukin 10-deficient mice (IL-10(-/-)) are a popular model used to dissect the mechanisms underlying inflammatory bowel diseases. The role of complement, a host defense mechanism that bridges the innate and adaptive immune systems, has not been described in this model. We therefore studied the effect of deficiency of properdin, a positive regulator of complement, on colitis in mice with the IL-10(-/-) background. METHODS: For acute colitis, IL-10(-/-) and IL-10/properdin double knockout (DKO) or radiation bone marrow-reconstituted chimeric mice, had piroxicam added to their powdered chow for 14 days. For chronic colitis, 2.5% dextran sodium sulfate was added to the animals' water for 4 days then the mice were killed 8 weeks later. Colons were assessed for inflammation, cell infiltration, and cytokine and complement measurements. Bacterial translocation was measured by cultivating bacteria from organs on Luria broth agar plates. RESULTS: C3a and C5a levels and C9 deposition were all increased in piroxicam-fed IL-10(-/-) mice compared with mice not fed piroxicam. Piroxicam-fed DKO mice lacked increased C5a and C9 deposition combined with exacerbated colitis, reduced numbers of infiltrating neutrophils, and markedly higher local and systemic bacterial numbers compared with IL-10(-/-) mice. Bone marrow cells from IL-10(-/-) mice were sufficient to restore protection against the heightened colitis in piroxicam-fed DKO mice. CONCLUSIONS: Complement is activated in the IL-10(-/-) mouse mucosa in a properdin-dependent manner. In the absence of terminal complement activation, the inflammation is heightened, likely due to a lack of neutrophil control over microbes escaping from the intestines.
BACKGROUND: Interleukin 10-deficient mice (IL-10(-/-)) are a popular model used to dissect the mechanisms underlying inflammatory bowel diseases. The role of complement, a host defense mechanism that bridges the innate and adaptive immune systems, has not been described in this model. We therefore studied the effect of deficiency of properdin, a positive regulator of complement, on colitis in mice with the IL-10(-/-) background. METHODS: For acute colitis, IL-10(-/-) and IL-10/properdin double knockout (DKO) or radiation bone marrow-reconstituted chimeric mice, had piroxicam added to their powdered chow for 14 days. For chronic colitis, 2.5% dextran sodium sulfate was added to the animals' water for 4 days then the mice were killed 8 weeks later. Colons were assessed for inflammation, cell infiltration, and cytokine and complement measurements. Bacterial translocation was measured by cultivating bacteria from organs on Luria broth agar plates. RESULTS: C3a and C5a levels and C9 deposition were all increased in piroxicam-fed IL-10(-/-) mice compared with mice not fed piroxicam. Piroxicam-fed DKO mice lacked increased C5a and C9 deposition combined with exacerbated colitis, reduced numbers of infiltrating neutrophils, and markedly higher local and systemic bacterial numbers compared with IL-10(-/-) mice. Bone marrow cells from IL-10(-/-) mice were sufficient to restore protection against the heightened colitis in piroxicam-fed DKO mice. CONCLUSIONS: Complement is activated in the IL-10(-/-) mouse mucosa in a properdin-dependent manner. In the absence of terminal complement activation, the inflammation is heightened, likely due to a lack of neutrophil control over microbes escaping from the intestines.
Authors: Alessandro Mangogna; Praveen M Varghese; Chiara Agostinis; Salman H Alrokayan; Haseeb A Khan; Cordula M Stover; Beatrice Belmonte; Anna Martorana; Giuseppe Ricci; Roberta Bulla; Uday Kishore Journal: Front Immunol Date: 2021-01-19 Impact factor: 7.561
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