MUC1 attenuates neutrophilic airway inflammation in asthma by reducing NLRP3 inflammasome-mediated pyroptosis through the inhibition of the TLR4/MyD88/NF-κB pathway

Abstract

Background Neutrophilic airway inflammation is a challenge in asthma management and is associated with poor patient prognosis. Mucin 1 (MUC1), which contains a cytoplasmic tail (MUC1-CT), has been found to mediate glucocorticoid sensitivity in asthma; however, its role in modulating neutrophilic airway inflammation in asthma remains unknown. Methods Human-induced sputum cells were collected from healthy participants (n = 12), patients with mild-to-moderate asthma (n = 34), and those with severe asthma (n = 18). In vitro human lung bronchial 1 epithelial cell line (BEAS-2B) was transfected with small interfering RNA against MUC1 (MUC1-siRNA) and then stimulated by lipopolysaccharide (LPS), where some cells were pretreated with a TLR4 inhibitor (TAK-242). In vivo mouse model of asthmatic neutrophil airway inflammation was induced by ovalbumin (OVA)/LPS. Some groups were intraperitoneally injected with MUC1-CT inhibitor (GO-203) and/or TAK-242 . Results The mRNA expression of MUC1 was downregulated in the induced sputum of patients with asthma and correlated with asthmatic neutrophilic airway inflammation. The mRNA expressions of TLR4, MyD88, nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3), caspase-1, interleukin (IL)-18, and IL-1β in induced sputum cells of patients with asthma were upregulated and related to the mRNA expression of MUC1. LPS activated the TLR4 pathway and NLRP3-mediated pyroptosis in BEAS-2B cells in vitro, which were significantly aggravated after MUC1-siRNA transfection. Furthermore, MUCl-CT interacted with TLR4, and the interaction between TLR4 and MyD88 was significantly increased after MUCl-siRNA transfection. Moreover, TAK-242 ameliorated TLR4/MyD88/nuclear factor kappa B (NF-κB) pathway activation, NLRP3 inflammasome-mediated pyroptosis, and neutrophilic inflammation exacerbated by MUC1 downregulation. GO-203 exacerbated TLR4/MyD88/NF-κB pathway activation in vivo, and NLRP3 inflammasome-mediated pyroptosis reduced in a mouse model of asthmatic neutrophil airway inflammation induced by OVA/LPS; these pathological changes were partially alleviated after TAK-242 application. Conclusion This study revealed that MUC1 downregulation plays an important role in asthmatic neutrophilic airway inflammation. MUC1-CT reduces NLRP3 inflammasome-mediated pyroptosis by inhibiting the activation of the TLR4/MyD88/NF-κB pathway, thereby attenuating neutrophil airway inflammation in patients with asthma.

B355252 Suppresses LPS-Induced Neuroinflammation in the Mouse Brain

“…Toll-like receptor 4 (TLR4) plays a crucial role in the immune system by recognizing pathogen-associated molecular patterns (PAMPs). Recent studies have shown that TLR4 exacerbates microglial pyroptosis through NLRP3 inflammasome activation [39,40]. Our results revealed that LPS increased the levels of TLR4, NLRP3, cleaved caspase-1, IL-1β, and IL-18, which is in agreement with previous publications showing activation of TLR4 and NLRP3 by LPS [28,29,41].…”

A bidirectional Mendelian randomization study investigating the relationship between genetically predicted systemic inflammatory regulators and chronic obstructive pulmonary disease

“…Lu Liu et al reported that MUC1, which may be an upstream regulator of TLR4/MyD88/NF-κB, was downregulated in asthma patients and further downregulated the expression of IL-18 by collecting sputum specimens from 64 individuals diagnosed with asthma. In addition, activation of TLR4/MyD88/NF-κB resulting from downregulation of MUC1 in asthma patients increased NLRP3 inflammasome-mediated focal death and inflammation in vitro [ 22 ]. Meng-Yu Zhang et al indicated that extracts from cigarette smoke stimulate NLRP3 inflammatory vesicles to recruit caspase-1 through ASC proteins, which cleave and activate IL-18 and IL-1β and ultimately lead to the death of bronchial epithelial cell [ 23 ].…”