Inorganic arsenic induces pyroptosis and pancreatic β cells dysfunction through stimulating the IRE1α/TNF-α pathway and protective effect of taurine

Abstract

Low-level inorganic arsenic (iAs) in drinking water is a risk factor for β cells dysfunction. Taurine (Tau) is a kind of semi-essential β amino acid, and beneficial for β cell function. However, the effects of Tau on arsenic trioxide (As₂O₃) induced β cells dysfunction and related mechanisms are still uncertain. Here, we found that Tau relieved As₂O₃-induced endoplasmic reticulum (ER) stress, inflammation and pyroptosis in rat pancreas. In INS-1 cells, with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inhibitor pretreatment, As₂O₃-induced activation of pyroptosis was decreased; with tumor necrosis factor-α (TNF-α) inhibitor pretreatment, As₂O₃-induced activation of NLRP3 inflammasome and pyroptosis were decreased; further, with the inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, As₂O₃-induced induction of TNF-α was decreased. Tau markedly protected As₂O₃-induced β cells dysfunction by reducing the phosphorylation of IRE1α, production of TNF-α, activation of NLRP3 inflammasome and pyroptosis. Our results revealed that ER stress dependent inflammation and pyroptosis are critical pathogenic components of As₂O₃-induced β cell dysfunction. Moreover, TNF-α was a critical signaling node that linked As₂O₃-induced ER stress and pyroptosis. Tau was an effective supplement against As₂O₃-induced β cells dysfunction through the pathway as mentioned above.

Keywords: Inorganic arsenic; Pyroptosis; Taurine; Tumor necrosis factor-α; β cells dysfunction.