The inflammasome pathway in stable COPD and acute exacerbations

Abstract

Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary and systemic inflammation that bursts during exacerbations of the disease (ECOPD). The NLRP3 inflammasome is a key regulatory molecule of the inflammatory response. Its role in COPD is unclear.We investigated the NLRP3 inflammasome status in: 1) lung tissue samples from 38 patients with stable COPD, 15 smokers with normal spirometry and 14 never-smokers; and 2) sputum and plasma samples from 56 ECOPD patients, of whom 41 could be reassessed at clinical recovery.We observed that: 1) in lung tissue samples of stable COPD patients, NLRP3 and interleukin (IL)-1β mRNA were upregulated, but both caspase-1 and ASC were mostly in inactive form, and 2) during infectious ECOPD, caspase-1, oligomeric ASC and associated cytokines (IL-1β, IL-18) were significantly increased in sputum compared with clinical recovery.The NLRP3 inflammasome is primed, but not activated, in the lungs of clinically stable COPD patients. Inflammasome activation occurs during infectious ECOPD. The results of this study suggest that the inflammasome participates in the inflammatory burst of infectious ECOPD.

Cigarette smoke inhibits the NLRP3 inflammasome and leads to caspase‐1 activation via the TLR4‐TRIF‐caspase‐8 axis in human macrophages

“…1,3 Upon the assembly of the complex, caspase-1 becomes active via autoproteolytic cleavage and in turn cleaves pro-IL-1β and pro-IL-18 into their released form and gasdermin D leading to pore formation. [3][4][5][6][7] It is well recognized that cigarette smoke leads to the abnormal inflammatory activation of the bronchial epithelium and to impaired macrophage responses. However, the role of the NLRP3 inflammasome in cigarette smoke-related diseases is still a matter of debate and available data are limited.…”

“…However, the role of the NLRP3 inflammasome in cigarette smoke-related diseases is still a matter of debate and available data are limited. [3][4][5][6][7] It is well recognized that cigarette smoke leads to the abnormal inflammatory activation of the bronchial epithelium and to impaired macrophage responses. [8][9][10] With respect to the NLRP3 inflammasome, growing evidence suggests that cigarette smoke activates the NLRP3 inflammasome in the lung epithelium, with increased expression of NLRP3, pro-IL-1β and caspase-1, higher caspase-1 activity and increased release of inflammasome-related cytokines IL-1β and IL-18.…”

Autoinflammatory disease in the lung

“…In addition to similarities in disease onset, the type of inflammation in COPD also bears many parallels with HAIDs. A strong IL‐1 β , IL‐6, IL‐18, IL‐27 and IL‐33 signature has been found in the lungs of individuals with COPD, as well as macrophage and neutrophilic infiltrations . A recent study by Faner et al ., described how the NLRP3 inflammasome is primed in COPD patients and that during exacerbations the pre‐primed NLRP3 inflammasome releases an excess of IL‐1 β family cytokines into the surrounding tissues.…”

“…A strong IL‐1 β , IL‐6, IL‐18, IL‐27 and IL‐33 signature has been found in the lungs of individuals with COPD, as well as macrophage and neutrophilic infiltrations . A recent study by Faner et al ., described how the NLRP3 inflammasome is primed in COPD patients and that during exacerbations the pre‐primed NLRP3 inflammasome releases an excess of IL‐1 β family cytokines into the surrounding tissues. Further evidence for IL‐1 β ‐driven inflammation in COPD has been demonstrated in a COPD mouse model, whereby tobacco smoke inhalation over 10 months was used to induce COPD in NLRP3 −/− and wild‐type mice .…”

Membrane microdomains regulate NLRP10- and NLRP12-dependent signalling in A549 cells challenged with cigarette smoke extract

“…Upon activation, either due to infection or tissue damage, some NLR family members can form inflammasome complex which regulates caspase-1 dependent maturation and release of pro-inflammatory cytokines IL-1β and IL-18. Evidence suggests the involvement of NLR/inflammasome-mediated signalling in eliciting inflammatory responses in tissues obtained from chronic smokers or patients with COPD (Faner et al 2016; Qian et al 2015). However, not all the NLR proteins have been studied with regards to cigarette smoke exposure.…”