Abstract
IL-33 is upregulated in ulcerative colitis and has a protective role in chemically-induced acute murine colitis. We aimed to determine whether IL-33 influences Il10−/− chronic colitis and its cellular source in health and during colitis. Il10−/−Il33−/− and Il10−/−Il33+/+ littermates developed colitis of similar severity. Colon Il33 was induced in WT and Il10−/− mice exposed to DSS, but not in unchallenged Il10−/− mice with colitis. Il33-citrine reporter mice showed that Il33-citrine colocalized with α-smooth muscle actin+ myofibroblasts and vimentin+ fibroblasts in WT mice. Citrine+CD74+CD90hi inflammatory fibroblasts were increased with DSS treatment. IL-1β induced Il33 expression in colon myofibroblasts, but colon Il33 expression did not differ between DSS-treated WT and Il1r1−/− mice. In conclusion, deficiency of IL-33 does not alter the severity of chronic colitis in Il10−/− mice. Induction of Il33 upon DSS exposure in WT and Il10−/− mice, but not in unchallenged Il10−/− mice, suggests epithelial injury induces colon IL-33. Fibroblasts are the primary colonic source of IL-33 and IL-33-expressing CD90hiCD74+ fibroblasts are increased during DSS-induced colitis. IL-1β induces Il33 in colon myofibroblasts in vitro, but signaling through the IL-1R1 is not necessary for induction of IL-33 in DSS-induced colitis.
Highlights
IL-33 is upregulated in ulcerative colitis and has a protective role in chemically-induced acute murine colitis
During acute colitis induced with DSS, we show there is an expansion of IL-33-producing inflammatory fibroblasts similar to those reported in human ulcerative colitis (UC)
We found that neither Il33 expression, nor IL-33 producing fibroblasts were increased during the development of chronic colitis in Il10-deficient mice, Il33 expression could be induced in Il10−/− mice by epithelial injury with DSS
Summary
IL-33 is upregulated in ulcerative colitis and has a protective role in chemically-induced acute murine colitis. Induction of Il33 upon DSS exposure in WT and Il10−/− mice, but not in unchallenged Il10−/− mice, suggests epithelial injury induces colon IL-33. A protective role has been shown for IL-33 in other models of colitis, we could find no differences in colitis development or severity in Il10−/− compared to Il10−/−Il33−/− mice. Using IL-33-citrine reporter mice (Il33Cit/+), we show that vimentin+CD90+ fibroblasts are the source of IL-33 at baseline and this population increases in DSS-induced. IL-1β induced IL-33 expression in vitro, using Il1r1−/− mice, we showed this signaling pathway is not required for Il33 induction during DSS-induced colitis. CD90+CD74+ inflammatory fibroblasts express IL-33 and are increased in DSS-induced colitis, indicating this population is likely responsible for the increases in Il33 in acute colitis induced by epithelial damage
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