Properdin regulation of complement activation affects colitis in interleukin 10 gene-deficient mice

Umang Jain, Craig A. Midgen, Wilhelm J. Schwaeble, Cordula M. Stover, Andrew W. Stadnyk

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish
Pages (from-to)1519-1528
Number of pages10
JournalInflammatory bowel diseases
Volume21
Issue number7
DOIs
StatePublished - May 19 2015

Keywords

  • C5a
  • IL-10
  • complement
  • neutrophils
  • properdin

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