Toll-like receptor 4-mediated endoplasmic reticulum stress induces intestinal paneth cell damage in mice following CLP-induced sepsis

Abstract

A marked elevation of TLR4 was observed in various organs of septic mice. The mechanism of TLR4 in intestinal epithelial cell damage in sepsis remains unclear. CLP mice models were used to assess the role of TLR4 in intestinal Paneth cell damage by histological, polymerase chain reaction, western-blot analyses. The ileal expression of TLR4 was increased by more than five-fold after CLP. CLP significantly increased 7-day mortality and was associated with a higher murine sepsis score (MSS), closely related with increased TLR4 expression. Histological staining revealed that a reduced number of Paneth cells, accompanied by reduced lysozyme and defensin alpha 5(DEF-5) expression as detected by PCR. Of note, the expression levels of ATF6, XBP1 and CHOP increased in the ileal of the sepsis group. Meanwhile, the uncleaved p90 ATF6 was markedly reduced and cleaved p50 ATF6 was increased in the sepsis group. Intriguingly, The TAK-242 had improved intestinal mucosal injury, reduced the expression of ATF6, XBP1 and CHOP and relieved the cleavage of ATF6. We found that increased the expression level of TLR4 in the ileal of CLP mice promoted the depletion of Paneth cell and reduced LYZ and DEF-5 expression. Furthermore, our findings suggested that TLR4-mediated the hyperactivation of ER stress, via activating the ATF6/CHOP pathway, might be one of the mechanisms associated with Paneth cells loss and dysfunction during intestinal barrier impairment of sepsis.

N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress

“…Delmotte et al found that TNF-α activates the ER stress pathway in human airway smooth muscle cells [38]. Sepsis is an uncontrolled systemic inflammatory response; inflammatory mediators such as TNF-α and IL-6 are elevated in sepsis, and it has been described that ER stress is dramatically induced in sepsis [39][40][41]. Inflammation is considered to be the major predisposing factor for skeletal muscle atrophy, which disturbs the homeostasis of the ER [42,43].…”

The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis

“…Paneth cells maintain gut mucosal integrity and homeostasis. In an experimental study, septic mice exhibited significantly fewer Paneth cells in the crypt, with disorganized granules or without granules [134]. In murine sepsis, increased ileal expression of TLR4 promoted the depletion of Paneth cells, and reduced lysozyme and defensin alpha 5 (DEF-5) expression exacerbated intestinal damage, and increased mortality rate.…”

“…In murine sepsis, increased ileal expression of TLR4 promoted the depletion of Paneth cells, and reduced lysozyme and defensin alpha 5 (DEF-5) expression exacerbated intestinal damage, and increased mortality rate. It has been suggested that TLR4 mediates the hyperactivation of ER stress, leading to Paneth cell loss and dysfunction during intestinal barrier impairment of sepsis [134].…”

New insights into the unfolded protein response (UPR)-anterior gradient 2 (AGR2) pathway in the regulation of intestinal barrier function in weaned piglets

“…Strategies to inhibit the ATF6 signaling pathway may be developed for the treatment of inflammatory bowel diseases ( Stengel et al., 2020 ). The ATF6/CHOP pathway may be associated with intestinal barrier dysfunction during sepsis ( Wang et al., 2022 ). Many studies have shown that inhibition of ATF6 expression can relieve ER stress and exert protective effects on the intestinal barrier function of SeNPs ( Pan et al., 2023 ), chlorogenic acid ( Song et al., 2022a ), and berberine ( Gong et al., 2022 ).…”