New insights into mechanisms controlling the NLRP3 inflammasome and its role in lung disease

Abstract

Inflammasomes are large macromolecular signaling complexes that control the proteolytic activation of two highly proinflammatory IL-1 family cytokines, IL-1β and IL-18. The NLRP3 inflammasome is of special interest because it can assemble in response to a diverse array of stimuli and because the inflammation it triggers has been implicated in a wide variety of disease pathologies. To avoid aberrant activation, the NLRP3 inflammasome is modulated on multiple levels, ranging from transcriptional control to post-translational protein modifications. Emerging genetic and pharmacological evidence suggests that NLRP3 inflammasome activation may also be involved in acute lung inflammation after viral infection and during progression of several chronic pulmonary diseases, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. Here, we review the most recent contributions to our understanding of the regulatory mechanisms controlling activation of the NLRP3 inflammasome and discuss the contribution of the NLRP3 inflammasome to the pathology of lung diseases.

Figure 1

Multiple levels of NLRP3 inflammasome regulation. Various types of cellular stress, including intracellular ROS production, lysosomal leakage, and ion fluxes (K⁺ efflux and Ca²⁺ influx), can trigger activation of the NLRP3 inflammasome. The events leading to NLRP3 activation appear to involve pathways mediating mitochondrial damage and the release of mitochondrial content into the cytosol [eg, oxidized DNA (oxDNA) and cardiolipin]. In addition, high levels of eATP activate NLRP3 after eATP binding the P2X7 receptor. Activation of NLRP3 leads to maturation and release of IL-1β and IL-18 cytokines after caspase-1–dependent proteolysis. In addition, capase-1 activation results in cell death via pyroptosis. The activation status of NLRP3 is modulated on multiple levels, to avoid aberrant activation. 1) In macrophages, NLRP3 (and pro-IL-1β) protein levels are controlled by a delayed transcriptional priming step mediated via activation of PRRs and cytokine receptors upstream of the transcription factor NFκB. 2) In resting myeloid cells, NLRP3 is negatively regulated via miR-223 at the post-transcriptional level. 3) Acutely, NLRP3 can be activated by BRCC3-dependent deubiquitination (de-Ub). The kinase activity of Syk, PKR, and TAK1 all play a role in NLRP3 activation, suggesting phosphorylation of NLRP3 may also be an activation requirement. 4) Type I IFN or IFNGR signaling leads to production of NO via activation of inducible nitric oxide synthase (iNOS). NO can inhibit NLRP3 inflammasome formation via SNO modification.

Figure 2

The NLRP3 inflammasome in lung inflammation and injury. Evidence from patients with lung diseases and experimental animal models suggests that a number of inhaled triggers can cause NLRP3 inflammasome activation in the lung, including cigarette smoke, asbestos, silica, bleomycin, and IAV. Inhaled silica crystals or asbestos fibers can induce NLRP3 activation directly via lysosomal damage and ROS production after phagocytosis by alveolar macrophages. The NLRP3 inflammasome can also be activated indirectly in the lung after the release of danger signals from dying or injured cells (eg, eATP and uric acid crystals). Activation of the NLRP3 inflammasome drives the production of IL-1β and IL-18 cytokines, causing the infiltration of additional immune cells and lymphocytes that sustain the inflammatory response potentially leading to chronic lung injury and pulmonary fibrosis.