Cigarette smoke inhibits the NLRP3 inflammasome and leads to caspase‐1 activation via the TLR4‐TRIF‐caspase‐8 axis in human macrophages. Issue 1 (8th December 2019)

• Record Type: Journal Article
• Authors: Buscetta, Marco; Di Vincenzo, Serena; Miele, Monica; Badami, Ester; Pace, Elisabetta; Cipollina, Chiara
• Is Part Of: FASEB journal. Volume 34:Issue 1(2020)
• Page Start: 1819
• Page End: 1832
• Publication Date: 2019-12-08
• Subjects: caspase‐8 -- inflammation -- IL‐1β -- IL‐18 -- metabolism -- smoking; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201901239R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: The NLRP3 inflammasome is formed by the sensor NLRP3, the adaptor ASC, and pro‐caspase‐1. Assembly and activation of the inflammasome trigger caspase‐1‐dependent cleavage of pro‐IL‐1β and pro‐IL‐18 into their secreted forms. Cigarette smoke is a risk factor for chronic inflammatory diseases and is associated with macrophage dysfunction. The impact of cigarette smoke on NLRP3‐dependent responses in macrophages is largely unknown. Herein, we investigated the effects of cigarette smoke extract (CSE) on the NLRP3 inflammasome in human monocyte‐derived macrophages (MDMs) and THP‐1 cells stimulated with lipopolysaccharide (LPS) and LPS plus the NLRP3 inflammasome activator ATP. We found that CSE inhibited the release of IL‐1β and IL‐18 as well as the expression of NLRP3 acting mainly at the transcriptional level. Interestingly, we found that CSE increased the caspase‐1 activity via an NLRP3‐independent and TLR4‐TRIF‐caspase‐8‐dependent pathway. Activation of caspase‐1 by CSE led to a reduction of the basal glycolytic flux and impaired glycolytic burst in response to LPS. Overall, our findings unveil novel pathways leading to immune‐metabolic alterations in human macrophages exposed to cigarette smoke. These mechanisms may contribute to macrophage dysfunction and increased risk of infection in smokers.