Alveolar macrophage pyroptosis and inflammatory signaling pathways

Alveolar macrophage pyroptosis is a highly pro-inflammatory form of programmed cell death that plays a pivotal role in the innate immune response and the pathogenesis of various pulmonary diseases (Shi et al., 2015, Nature). This process is primarily initiated by the activation of the NLRP3 inflammasome in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), such as silica particles or viral proteins (He et al., 2015, Nature). Upon activation, the inflammasome recruits and activates Caspase-1, which processes pro-interleukin-1β and pro-interleukin-18 into their mature, secreted forms and cleaves Gasdermin D (GSDMD). The resulting GSDMD N-terminal fragments form large pores in the plasma membrane, leading to the rapid release of intracellular contents and cytokines, followed by osmotic cell lysis (Wu et al., 2020, Front. Immunol.). While this mechanism is essential for defense against certain pathogens, excessive pyroptosis in alveolar macrophages drives the hyper-inflammation seen in acute respiratory distress syndrome (ARDS), silicosis, and severe COVID-19. Therapeutic strategies targeting this pathway, including NLRP3 inhibitors like MCC950 and Caspase-1 inhibitors like VX-765, are being investigated to mitigate tissue damage and improve outcomes in inflammatory lung conditions (Coll et al., 2015, Nat. Med.).

Other names

Alveolar macrophage pyroptosisNLRP3-Caspase-1-GSDMD axis in lungMacrophage-mediated inflammatory lung injuryPyroptotic signaling in alveolar macrophages

Inhibition of the NLRP3 inflammasome assembly, blockade of Caspase-1 activation, or prevention of Gasdermin D pore formation to reduce the release of pro-inflammatory cytokines and prevent lytic cell death.