Molecular mechanisms and roles of pyroptosis in acute lung injury

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which are characterized by excessive inflammation and accompanied by diffuse injury of alveoli, can result in severe respiratory failures. The morbidity and mortality of patients remain high because the major treatments for ALI/ARDS are mainly supportive due to the lack of effective therapies. Numerous studies have demonstrated that the aggravation of coronavirus disease 2019 (COVID-19) leads to severe pneumonia and even ARDS. Pyroptosis, a biological process identified as a type of programed cell death, is mainly triggered by inflammatory caspase activation and is directly meditated by the gasdermin protein family, as well as being associated with the secretion and release of pro-inflammatory cytokines. Clinical and experimental evidence corroborates that pyroptosis of various cells in the lung, such as immune cells and structural cells, may play an important role in the pathogenesis of "cytokine storms" in ALI/ARDS, including those induced by COVID-19. Here, with a focus on ALI/ARDS and COVID-19, we summarized the recent advances in this field and proposed the theory of an inflammatory cascade in pyroptosis to identify new targets and pave the way for new approaches to treat these diseases.

Figure 1

The mechanisms of pyroptosis. PAMPs and DAMPs stimulate cells and activate canonical inflammasomes such as NLRP3. Then mature caspase-1 cleaves GSDMD into GSDMD-N and promotes secretion of IL-1β and IL-18. GSDMD-N binds to the membrane and forms a pore, which mediates K⁺ efflux, Na⁺ influx, water influx, and cytokine release. LPS can directly activate caspase-4/-5/-11, which can promote the cleavage of GSDMD. Coincidently, caspase-3 cleaves GSDME and acquires GSDME-N, which plays the same role as GSDMD-N. Caspase-8 acts as a positive upstream regulator of caspase-1 and caspase-3. When caspase-1 is inhibited, caspase-8 can directly cleave GSDMD. There also exists a rescue mechanism, whereby ESCRT-III can be recruited to the pores on the membrane to repair them, induced by Ca²⁺ inflow. The figure was created with BioRender.com. AIM2: Absent in melanoma-2; ASC: Apoptosis-associated speck-like protein; CLR: C-type lectin receptor; DAMPs: Damage-associated molecular patterns; ESCRT-III: Endosomal sorting complexes required for transport-III; GSDMD: Gasdermin D; GSDME: Gasdermin E; IL-1β: Interleukin-1β; IL-18: Interleukin-18; LPS: Lipopolysaccharide; NLRC: Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruitment domain-containing; NLRP: Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing; PAMPs: Pathogen-associated molecular patterns; TLR: Toll-like receptor.

Figure 2

Pyroptosis in different cell types of the lung and inflammatory cascade. When pathogens invade the lung, monocytes and macrophages are activated and pyroptosis occurs. The released inflammatory cytokines destroy the stability of the lung tissue microenvironment and cause pyroptosis in other lung immune cells and structural cells, forming a cascade reaction and aggravating lung injury. NETs released from neutrophils can also activate macrophages to induce pyroptosis. Pulmonary epithelial and endothelial cells suffer from pyroptosis, dysfunction, and impaired blood–gas barrier, leading to aggravation of ALI. The figure was created with BioRender.com. ALI: Acute lung injury; CCL7: Chemokine (C-C motif) ligand 7; CXCL12: Chemokine (C-X-C motif) ligand 12; LPS: Lipopolysaccharide; IL: Interleukin; NETosis: Neutrophil extracellular traps release; TNF-α: Tumor necrosis factor-α.

Figure 3

SARS-CoV-2-induced mechanisms of inflammasome activation. SARS-CoV-2 enters cells via ACE2 and TLR-4. After SARS-CoV-2 interacts with ACE2 and TLR-4, NLRP3 inflammasomes are activated, leading to pyroptosis. Then numerous inflammatory cytokines are released and aggravate lung injury. The figure was created with BioRender.com. ACE2: Angiotensin-converting enzyme 2; GSDMD: Gasdermin; IL: Interleukin; NLRP3: Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; TLR-4: Toll-like receptor 4; TMPRSS2: Transmembrane protease serine 2; TNF-α: Tumor necrosis factor-α.