Inflammasomes in COPD and neutrophilic asthma

Inflammasomes have recently been identified to be critical and potent inducers of inflammation that when overactive may be targeted therapeutically in inflammatory diseases. Inflammasomes are multiprotein signalling complexes that control the maturation and release of pro-inflammatory cytokines in response to numerous exogenous, endogenous and pathogenic danger signals (figure 1).1 They mediate host responses, particularly interleukin (IL)-1β release and neutrophilic inflammatory responses, which are essential for protection against infection. However, recent evidence demonstrates that excessive inflammasome activation is a feature of numerous inflammatory diseases including COPD, neutrophilic asthma, idiopathic pulmonary fibrosis, cystic fibrosis, acute respiratory distress syndrome (ARDS) and respiratory infections (table in figure 1). Infections are the most widely recognised activators of inflammasomes; however, this field has recently been reviewed extensively and is beyond the scope of this article. Their roles in ARDS and potential for therapeutic targeting are well established.2 It is now emerging that inflammasomes are likely involved in the pathogenesis of COPD and asthma, and further investigation is urgently needed. Figure 1 Potential role for inflammasome activation in COPD and neutrophilic asthma. Numerous exogenous, endogenous and pathogenic danger signals (eg, ATP, monosodium urate crystals (MSU)) in the airways induce the assembly and activation of the inflammasome complex and synthesis of pro-interleukin (IL)-1β. Inflammasome activation by pathogen-associated molecular patterns (PAMPs) (eg, lipopolysaccharide (LPS) and peptidoglycan) results in proteolytic cleavage and activation of pro-caspase-1. Active caspase-1 in turn mediates the subsequent cleavage of pro-IL-1β that leads to the production and release of IL-1β and other pro-inflammatory mediators and cellular contents, including IL-18 and adaptor protein apoptosis-associated speck-like containing a caspase recruitment domain (ASC) specks. Excessive release of active IL-1β and ASC specks promotes neutrophil-dominated inflammatory responses in the airways that contribute to the pathogenesis of COPD and neutrophilic asthma. Complex interactions between inflammasomes, IL-1β, its receptors and intracellular …