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Contributions of HO-1-Dependent MAPK to Regulating Intestinal Barrier Disruption

Zhenling Zhang1, Qiuping Zhang2, Fang Li3

  • 1Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian116011, China.

Biomolecules & Therapeutics
|October 23, 2020
PubMed

Insights

Heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal barrier by inhibiting the MAPK pathway, reducing cell damage and tight junction disruption. Targeting this HO-1-MAPK axis may improve intestinal disease therapies.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Cell Biology

Background:

  • The mitogen-activated protein kinase (MAPK) pathway regulates intestinal epithelial barrier function, influencing tight junctions (TJs) and cell damage.
  • Heme oxygenase-1 (HO-1) and its product carbon monoxide (CO) are known to protect the intestinal barrier, but the underlying molecular mechanisms require further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanism by which HO-1 and CO protect the intestinal epithelial barrier function.
  • To determine the role of the MAPK pathway in HO-1-mediated protection of the intestinal barrier.

Main Methods:

  • Caco-2 cell monolayers were treated with TNF-α and transfected with HO-1 or sh-HO-1 plasmids to study MAPK activation and barrier permeability.
  • Wild-type and HO-1-deficient mice were treated with carbon tetrachloride (CCl4) and administered HO-1 inducers (CoPP) or inhibitors (ZnPP), or CO-releasing molecules (CORM-2) to assess mucosal barrier integrity and MAPK activation.

Main Results:

  • TNF-α induced TJ disruption, cleaved caspase-3 expression, and phosphorylation of ERK, p38, and JNK.
  • HO-1 expression inhibited TNF-α-induced TJ disruption, cleaved caspase-3, and MAPK phosphorylation in an HO-1-dependent manner.
  • CoPP and CORM-2 ameliorated CCl4-induced intestinal injury, TJ disruption, and MAPK activation, while ZnPP reversed these effects. HO-1 deficient mice showed increased barrier disruption and MAPK activation.

Conclusions:

  • HO-1-dependent inhibition of MAPK signaling preserves intestinal mucosal barrier integrity by preventing TJ dysregulation and epithelial cell damage.
  • Targeting the gut HO-1-MAPK axis presents a promising therapeutic strategy for intestinal diseases.
Keywords:
HO-1Inflammatory bowel diseaseIntestinal barrier functionMAPKTight junction

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