Mitochondrial Regulation of Inflammasome Activation in Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by enhanced chronic airway and lung inflammatory responses to noxious particles or gases. It is a major unmet medical need worldwide, and in Western society is strongly associated with exposure to cigarette smoke (CS). CS-induced inflammation is believed to be a key immune driver in the pathogenesis of COPD. Since the concept of inflammasomes was first introduced nearly a decade ago, these have been increasingly recognized as a central player in innate immune and inflammatory responses. In addition, studies have emerged demonstrating that mitochondrial innate immune signaling plays an important role in CS-induced inflammasome activation, pulmonary inflammation and tissue remodeling responses. Here, recent discoveries about inflammasome activation and mitochondrial biology and their role in COPD pathogenesis are reviewed. In addition, the current limitations of our understanding of this theme and future research directions are discussed.

Fig. 1

The hypothetical mechanism of CS-induced inflammasome activation and its contribution to COPD pathogenesis. CS, containing more than 4,000 chemicals, may stimulate multiple DAMP-mediated pathways. These pathways might converge on MAVS. MAVS-dependent inflammasome activation results in the activation of the proinflammatory cytokines IL-1β and IL-18, and PKR may play an important regulatory role. NLRX1 may mediate a critical inhibitory role on the MAVS-mediated activation of inflammasomes. See main text for the explanation in detail.