Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis

P Alex, M Ye, NC Zachos, J Sipes… - The Journal of …, 2010 - journals.aai.org
P Alex, M Ye, NC Zachos, J Sipes, T Nguyen, M Suhodrev, L Gonzales, Z Arora, T Zhang…
The Journal of Immunology, 2010journals.aai.org
Although the intracellular Cl−/H+ exchanger Clc-5 is expressed in apical intestinal endocytic
compartments, its pathophysiological role in the gastrointestinal tract is unknown. In light of
recent findings that CLC-5 is downregulated in active ulcerative colitis (UC), we tested the
hypothesis that loss of CLC-5 modulates the immune response, thereby inducing
susceptibility to UC. Acute dextran sulfate sodium (DSS) colitis was induced in Clcn5
knockout (KO) and wild-type (WT) mice. Colitis, monitored by disease activity index …
Abstract
Although the intracellular Cl−/H+ exchanger Clc-5 is expressed in apical intestinal endocytic compartments, its pathophysiological role in the gastrointestinal tract is unknown. In light of recent findings that CLC-5 is downregulated in active ulcerative colitis (UC), we tested the hypothesis that loss of CLC-5 modulates the immune response, thereby inducing susceptibility to UC. Acute dextran sulfate sodium (DSS) colitis was induced in Clcn5 knockout (KO) and wild-type (WT) mice. Colitis, monitored by disease activity index, histological activity index, and myeloperoxidase activity were significantly elevated in DSS-induced Clcn5 KO mice compared with those in WT mice. Comprehensive serum multiplex cytokine profiling demonstrated a heightened Th1–Th17 profile (increased TNF-α, IL-6, and IL-17) in DSS-induced Clcn5 KO mice compared with that in WT DSS colitis mice. Interestingly, Clcn5 KO mice maintained on a high vitamin D diet attenuated DSS-induced colitis. Immunofluorescence and Western blot analyses of colonic mucosa validated the systemic cytokine patterns and further revealed enhanced activation of the NF-κB pathway in DSS-induced Clcn5 KO mice compared with those in WT mice. Intriguingly, high baseline levels of IL-6 and phospho-IκB were observed in Clcn5 KO mice, suggesting a novel immunopathogenic role for the functional defects that result from the loss of Clc-5. Our studies demonstrate that the loss of Clc-5 1) exhibits IL-6–mediated immunopathogenesis, 2) significantly exacerbated DSS-induced colitis, which is influenced by dietary factors, including vitamin D, and 3) portrays distinct NF-κB–modulated Th1–Th17 immune dysregulation, implying a role for CLC-5 in the immunopathogenesis of UC.
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