Abstract
Adiponectin demonstrates beneficial effects in various metabolic diseases, including diabetes, and in bowel cancer. Recent data also suggest a protective role in colitis. However, the precise molecular mechanisms by which adiponectin and its receptors modulate colitis and the nature of the adaptive immune response in murine models are yet to be elucidated. Adiponectin knock-out mice were orally administered dextran sulfate sodium for 7 days and were compared with wild-type mice. The severity of disease was analyzed histopathologically and through cytokine profiling. HCT116 colonic epithelial cells were employed to analyze the in vitro effects of adiponectin and AdipoR1 interactions in colonic injury following dextran sulfate sodium treatment. Adiponectin knock-out mice receiving dextran sulfate sodium exhibited severe colitis, had greater inflammatory cell infiltration, and an increased presence of activated B cells compared with controls. This was accompanied by an exaggerated proinflammatory cytokine profile and increased STAT3 signaling. Adiponectin knock-out mouse colons had markedly reduced proliferation and increased epithelial apoptosis and cellular stress. In vitro, adiponectin reduced apoptotic, anti-proliferative, and stress signals and restored STAT3 signaling. Following the abrogation of AdipoR1 in vitro, these protective effects of adiponectin were abolished. In summary, adiponectin maintains intestinal homeostasis and protects against murine colitis through interactions with its receptor AdipoR1 and by modulating adaptive immunity.
Highlights
Adiponectin demonstrates beneficial effects in various metabolic diseases, including diabetes, and in bowel cancer
As would be expected from the known anti-inflammatory effects of adiponectin, colonic pathology analyses of APN knock-out (APN-KO) mice treated with dextran sulfate sodium (DSS) revealed distorted epithelial crypt architecture accompanied by a significant immune cell infiltrate compared with all other groups (WT control, WT DSS, and APN-KO control; Fig. 1A)
As shown by CD45R staining and dual staining for CD45R and CD40, APN-KO DSS-treated mice had increased numbers of B cells and an activated B-cell infiltrate as indicated by CD45R and CD40 co-localization, which was 2-fold less in WT mice (Fig. 6, A and B). This observation was confirmed by qRTPCR analysis showing significantly greater gene expression of CD19 and CD40 in APN-KO colitic mice compared with WT mice treated with DSS (p Ͻ 0.05 and p Ͻ 0.01, respectively; Fig. 6C)
Summary
Adiponectin demonstrates beneficial effects in various metabolic diseases, including diabetes, and in bowel cancer. Adiponectin knock-out mice receiving dextran sulfate sodium exhibited severe colitis, had greater inflammatory cell infiltration, and an increased presence of activated B cells compared with controls. This was accompanied by an exaggerated proinflammatory cytokine profile and increased STAT3 signaling. Adiponectin modulates inflammatory responses in a number of gut diseases, including inflammatory bowel disease and colorectal cancer [24, 25] It remains unresolved how APN influences IEC survival and modulates immune responses during colitis. We observed in APN-KO mice increased IEC damage, B-cell accumulation, and up-regulated STAT3 signaling These effects were modulated through its receptor AdipoR1. Our results suggest that limited levels of APN modulate colitis progression through multiple actions
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