Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in mice
Open Access
- 1 October 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (10), 5197-5208
- https://doi.org/10.1172/jci138697
Abstract
The tight junction protein claudin-2 is upregulated in disease. Although many studies have linked intestinal barrier loss to local and systemic disease, these have relied on macromolecular probes. In vitro analyses show however that these probes cannot be accommodated by size- and charge-selective claudin-2 channels. We sought to define the impact of claudin-2 channels on disease. Transgenic claudin-2 overexpression or IL-13-induced claudin-2 upregulation increased intestinal small cation permeability in vivo. IL-13 did not however affect permeability in claudin-2-knockout mice. Claudin-2 is therefore necessary and sufficient to effect size- and charge-selective permeability increases in vivo. In chronic disease, T-cell transfer colitis severity was augmented or diminished in claudin-2 transgenic or knockout mice, respectively. We translated in vitro data suggesting that casein kinase-2 (CK2) inhibition blocks claudin-2 channel function and found that CK2 inhibition prevented IL-13-induced, claudin-2-mediated permeability increases in vivo. In chronic immune-mediated colitis, CK2 inhibition attenuated progression in claudin-2-sufficient, but not claudin-2-knockout, mice, i.e., the effect was claudin-2-dependent. Paracellular flux mediated by claudin-2 channels can therefore promote immune-mediated colitis progression. Although the mechanisms by which claudin-2 channels intensify disease remain to be defined, these data suggest that claudin-2 may be an accessible target in immune-mediated disorders, including inflammatory bowel disease.Keywords
Funding Information
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK61931,R01DK68271,R24DK099803,P30DK034854)
- U.S. Department of Defense (PR181271)
- Crohn's and Colitis Foundation (NA)
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