Influenza a virus triggers acute exacerbation of chronic obstructive pulmonary disease by increasing proinflammatory cytokines secretion via NLRP3 inflammasome activation

Abstract

Background Influenza A virus (IAV) triggers acute exacerbation of chronic obstructive pulmonary disease (AECOPD), but the molecular mechanisms remain unclear. In this study, we investigated the role of IAV induced NLRP3 inflammasome activation to increase airway inflammation response in the progression of AECOPD. Methods Human bronchial epithelial cells were isolated and cultured from normal and COPD bronchial tissues and co-cultured with IAV. The NLRP3 inflammasome associated genes were identified using RNA sequencing, and the expressions of NLRP3 inflammasome components were measured using qRT-PCR and western blot after cells were transfected with siRNA and treated with MCC950. Moreover, IAV-induced COPD rat models were established to confirm the results; 37 AECOPD patients were included to measure the serum and bronchoalveolar lavage fluid (BALF) of interleukin (IL)-18 and IL-1β. Results Increased levels of NLRP3 inflammasome components were not seen until 6 h post-inoculation in normal cells. However, both cell groups reached peak NLRP3 level at 12 h post-inoculation and maintained it for up to 24 h. ASC, Caspase-1, IL-1β and IL-18 were also elevated in a similar time-dependent pattern in both cell groups. The mRNA and protein expression of the NLRP3 inflammasome components were decreased when COPD cells treated with siRNA and MCC950. In COPD rats, the NLRP3 inflammasome components were elevated by IAV. MCC950 alleviated lung damage, improved survival time, and reduced NLRP3 inflammasome components expression in COPD rats. Additionally, the serum and BALF levels of IL-1β and IL-18 were increased in AECOPD patients. Conclusions NLRP3 inflammasome is activated in COPD patients as a pre-existing condition that is further exacerbated by IAV infection.

Quantitative proteomics of differentiated primary bronchial epithelial cells from chronic obstructive pulmonary disease and control identifies potential novel host factors post-influenza A virus infection

“…Exacerbation, defined as a sudden worsening of clinical manifestations and decrease in lung function, is related to a significantly worse survival outcome ( Viniol and Vogelmeier, 2018 ), and the influenza virus is one of the respiratory viruses triggering COPD exacerbations ( Bouquet et al, 2020 ). However, the underlying mechanisms of acute COPD exacerbations by influenza viruses have not been fully elucidated ( Decramer et al, 2012 ; Viniol and Vogelmeier, 2018 ; Ji et al, 2022 ; Wu et al, 2022 ).…”

Human cytomegalovirus infection activates NLRP3 inflammasome by releasing mtDNA into the cytosol in human THP‐1 cells

“…8 The important sensor in inflammasome is the NLR family pyrin domain containing 3 (NLRP3), which is involved in some viral infections such as the Ebola virus, Epstein-Barr virus, or influenza virus. [9][10][11] However, it is still less clear whether HCMV infection can activate the NLRP3 inflammasome in THP-1 monocytes.…”

“…Inflammasome, consisting of a pattern recognition receptor, an adaptor protein, and procaspase‐1, can regulate the maturation and secretion of inflammatory cytokines to fight viruses 8 . The important sensor in inflammasome is the NLR family pyrin domain containing 3 (NLRP3), which is involved in some viral infections such as the Ebola virus, Epstein–Barr virus, or influenza virus 9–11 . However, it is still less clear whether HCMV infection can activate the NLRP3 inflammasome in THP‐1 monocytes.…”