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Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in
Preeti Raju1, Nitesh Shashikanth1, Pei-Yun Tsai2
1Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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 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.
Insights
Claudin-2 channels increase intestinal permeability in disease. Inhibiting casein kinase-2 (CK2) blocks these channels, offering a potential therapeutic target for inflammatory bowel disease.
Area of Science:
- Gastroenterology
- Cell Biology
- Immunology
Background:
- The tight junction protein claudin-2 is upregulated in various diseases.
- Previous studies on intestinal barrier loss used macromolecular probes, which are unsuitable for claudin-2 channels.
- Claudin-2 channels selectively control the passage of small ions.
Purpose of the Study:
- To investigate the role of claudin-2 channels in disease pathogenesis.
- To determine if claudin-2 is necessary and sufficient for altered intestinal permeability.
- To evaluate the therapeutic potential of targeting claudin-2 channel function.
Main Methods:
- Overexpression of claudin-2 in transgenic mice.
- Induction of claudin-2 upregulation using IL-13.
- Assessment of intestinal permeability in claudin-2 knockout and wild-type mice.
- Inhibition of casein kinase-2 (CK2) to block claudin-2 channel activity.
- Modeling chronic immune-mediated colitis via T cell transfer.
Main Results:
- Claudin-2 overexpression and IL-13 treatment increased intestinal small cation permeability in vivo.
- IL-13 did not affect permeability in claudin-2 knockout mice, confirming claudin-2's necessity.
- CK2 inhibition prevented IL-13-induced permeability increases and attenuated chronic colitis progression in a claudin-2-dependent manner.
- Colitis severity was altered in claudin-2 transgenic and knockout mice, indicating claudin-2's role in disease severity.
Conclusions:
- Claudin-2 channels are necessary and sufficient for increased intestinal permeability in vivo.
- Paracellular flux mediated by claudin-2 channels can exacerbate immune-mediated colitis.
- Targeting claudin-2 channel function, for example, via CK2 inhibition, shows promise for treating inflammatory bowel disease and other immune-mediated disorders.
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