HSP60 regulates the cigarette smoke-induced activation of TLR4-NF-κB-MyD88 signalling pathway and NLRP3 inflammasome

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by increased cellular stress and inflammation. Heat shock protein 60 (HSP60) is a highly conserved stress protein that acts as a cellular “danger” signal for immune reactions. In this study, we investigated the role of HSP60 in COPD and explored the underlying mechanisms. Expression levels of HSP60 in patients with acute exacerbation of COPD (AECOPD), stable COPD, and healthy people were detected by Western blotting and enzyme-linked immunosorbent assay (ELISA). Moreover, the effect and molecular mechanism of HSP60 in COPD were studied in cigarette smoke (CS)-treated C57BL/6 mice and macrophages. The results showed significant upregulation of HSP60 expression in the peripheral blood mononuclear cells (PBMCs) and sera of patients with AECOPD compared to those with stable COPD or healthy people. CS induced the expression of HSP60 in the COPD mouse model, accelerated the activation of toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3) signalling pathways, promoted the increase of inflammatory cells in alveolar lavage fluid and serum inflammatory factors, and induced destruction of lung tissue structure. Furthermore, HSP60 knockdown affected TLR4 and MyD88 expression, IκBα degradation, and nuclear localization of NF-κB and NLRP3 inflammasome activity. Our study revealed that CS stimulates the expression of HSP60, activating the TLR4-MyD88-NF-κB signalling pathway and the NLRP3 inflammasome.