Pyroptosis and respiratory diseases: A review of current knowledge

Abstract

Pyroptosis is a relatively newly discovered programmed cell death accompanied by an inflammatory response. In the classical view, pyroptosis is mediated by caspases-1,-4,-5,-11 and executed by GSDMD, however, recently it was demonstrated that caspase-3 and-8 also participate in the process of pyroptosis, by cleaving GSDMD/E and GSDMD respectively. Different from autophagy and apoptosis, many pores are formed on the cell membrane during pyroptosis, which makes the cell membrane lose its integrity, eventually leading to the release of cytokines interleukin(IL)-1β and IL-18. When the body is infected with pathogens or exposed to some stimulations, pyroptosis could play an immune defense role. It is found that pyroptosis exists widely in infectious and inflammatory respiratory diseases such as acute lung injury, bronchial dysplasia, chronic obstructive pulmonary disease, and asthma. Excessive pyroptosis may accompany airway inflammation, tissue injury, and airway damage, and induce an inflammatory reaction, leading to more serious damage and poor prognosis of respiratory diseases. This review summarizes the relationship between pyroptosis and related respiratory diseases.

Keywords: NLRP3; caspase; infection; inflammation; pyroptosis; respiratory diseases.

Figure 1

Pyroptosis is mediated by several pathways: (A) In the classical pyroptosis signaling pathway, NLRP3 is activated under the stimulation of PAMPs/DAMPs as well as cytoplasmic disturbances, termed as homeostasis altering molecular properties (HAMPs), then the PYD at the NLRP3 N-terminal binds to the ASC protein containing the PYD domain, and the CARD of ASC binds to the CARD of pro-caspase-1 to form a multi-protein complex and activate Caspase-1. Activated Caspase-1 cleaves GSDMD and divides GSDMD protein into lipophilic N-terminal domain and hydrophilic C-terminal domain, the N-terminal domain binds to the lipids on the cell membrane to form pores, causing the release of cell contents. On the other hand, the N-terminal produced by cleavage from GSDMD has another function for promoting the proteolytic activation of caspase-1, helps to form active IL-1β and IL-18. At the same time, cells release IL-1β and IL-18 released to the outside of the cell during pyroptosis recruit more inflammatory cells and expand the inflammatory response. (B) In the non-classicial pyroptosis signaling pathway, Caspase-4, 5, and 11 are activated under the stimulation of bacteria and other signals. The GSDMD is cleaved by the activated Caspase-4, 5, and 11 to form the lipophilic N-terminal domain, inducing cell membrane perforation and causing inflammation. (C) In Caspase-8-dependent pyroptosis signaling pathway, Caspase-8 is activated by Yersinia via the TLR4/RIP1 signaling pathway to induce pyroptosis. (D) In Caspase-3-dependent pyroptosis signaling pathway, Caspase-3 promotes the recruitment of the GSDME-N domain to the cell membrane by cutting off GSDME and induces the formation of cell pores, thus leading to pyroptosis.

Figure 2

The pathological factors participate in the activation of NLRP3 inducing pyroptosis in many kinds of airway cells, such as pulmonary vascular endothelial cells, bronchial epithelial cells, neutrophils, and alveolar macrophages. The excessive pyroptosis results in the enhanced release of IL-1β and IL-18, which recruit more inflammatory cells and release of other cytokines such as TNF-α, IL-6, IL-8, IL-10, IL-17 and etc., leading to associated pathological consequences, such as airway cell injury and inflammation, airway cell repair disorder, mucus hypersecretion, AHR, and airway remodeling. The pathological changes caused by pyroptosis participates in the pathogenesis of many respiratory diseases such as ARDS, asthma, BO, COPD and so on.