Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in mice.

The Journal of Clinical Investigation
Preeti RajuJerrold R Turner

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 the in vitro observation that casein kinase-2 (CK2) inhibition blocks claudin-2 channel function to prevent acute, 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 cl...Continue Reading

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Citations

Aug 25, 2020·The Journal of Clinical Investigation·Kim E Barrett
Mar 25, 2021·American Journal of Physiology. Gastrointestinal and Liver Physiology·Paula Marincola SmithR Daniel Beauchamp
May 18, 2021·Signal Transduction and Targeted Therapy·Christian BorgoMaria Ruzzene
Jun 10, 2021·Current Protocols·Nitesh ShashikanthJerrold R Turner
Oct 9, 2021·Journal of Molecular Histology·Siwen TangJinghua Liang

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Methods Mentioned

BETA
transgenic
fluorescence recovery after photobleaching

Software Mentioned

MetaMorph
MediaCybernetics
ImageJ
Image Studio ( LI )

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