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

Philip Alex, Mei Ye, Nicholas C. Zachos, Jennifer Sipes, Thuan Nguyen, Maxim Suhodrev, Liberty Gonzales, Zubin Arora, Ting Zhang, Michael Centola, Sandra E. Guggino, Xuhang Li

Research output: Contribution to journalArticle

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 WTDSS 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.

Original languageEnglish (US)
Pages (from-to)3988-3996
Number of pages9
JournalJournal of Immunology
Volume184
Issue number7
DOIs
StatePublished - Apr 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Alex, P., Ye, M., Zachos, N. C., Sipes, J., Nguyen, T., Suhodrev, M., Gonzales, L., Arora, Z., Zhang, T., Centola, M., Guggino, S. E., & Li, X. (2010). Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis. Journal of Immunology, 184(7), 3988-3996. https://doi.org/10.4049/jimmunol.0901657