Dysfunction of epithelial permeability barrier induced

Airway and intestinal epithelial permeability barriers are crucial in epithelial homeostasis. High mobility group box 1 (HMGB1), increased by various stimuli, is involved in the induction of airway inflammation, as well as the pathogenesis of inflammatory bowel disease. HMGB1 enhances epithelial hyperpermeability.

Two-and-a-half dimensional (2.5D) culture assays are experimentally convenient and induce cells to form a more physiological tissue architecture than 2D culture assays for molecular transfer mechanism analysis.

In 2.5D culture, treatment with HMGB1 induced permeability of FITC-dextran into the lumen formed by human lung, nasal and intestinal epithelial cells.

The tricellular tight junction molecule angulin-1/LSR is responsible for the epithelial permeability barrier at tricellular contacts and contributes to various human airway and intestinal inflammatory diseases.

In this review, we indicate the mechanisms including angulin-1/LSR and multiple signaling in dysfunction of the epithelial permeability barrier induced by HMGB1 in 2.5D culture of human airway and intestinal epithelial cells.

In patients with severe case of COVID-19, serum HMGB is elevated and exogenous HMGB1 induces the expression of SARS-CoV-2 entry receptor ACE2 in alveolar epithelial cells in an AGER-dependent manner.

 An increased concentration of HMGB1 in the serum may contribute to several infectious and inflammatory diseases of the airway and intestine.

In HNECs treated with HMGB1, upregulation of the COVID-19-related genes cathepsin L (CTSL) and furin is observed104. Cysteine protease CTSL expression is upregulated during chronic inflammation and is involved in processing the COVID-19 spike protein.

The protease furin is also involved in mediating SARS-CoV-2 entry.109 It is possible that HMGB1 induced by COVID-19 infection may increase in HNECs and disrupt the epithelial permeability barriers. Thus, HMGB1 in the airway and intestine may be a therapeutic target in the severe inflammation of COVID-19.