Table 1.

Regulatory roles of noncanonical inflammasomes in inflammatory lung diseases.

Diseases	Inflammasomes	Roles	Models	Ref.
Asthma	Caspase-11	HDM and allergy-associated cytokines increased the expression of caspase-11 in mouse BMDMs. Production of pro-inflammatory cytokines decreased in caspase-11−/− BMDMs in response to HDM. Total cellular infiltration into BALF and pro-inflammatory cytokine levels in the BALF were significantly decreased in caspase-11−/− mice in response to HDM. Histological signs of lung inflammation were reduced in caspase-11−/− mice in response to HDM.	Mouse BMDMs HDM-induced allergic asthma mice	[32]
	Caspase-4	Neutrophilic asthma patients showed a marked increase in caspase-4 expression and elevated production of IL-1β and IL-18. Elevated expression and production of caspase-4, IL-1β, and IL-18 were not observed in other asthma types, such as eosinophilic and paucigranulocytic asthma.	Human neutrophilic asthma patients	[33]
	Caspase-4/11	Caspase-11 expression was upregulated in OVA-induced allergic lung inflammation in mice. Caspase-11 deficiency protected allergic lung inflammation in mice. PGE2 inhibited caspase-11 expression and activation of caspase-11 noncanonical inflammasome in mouse BMDMs. PGE2 inhibited caspase-11 and caspase-4 noncanonical inflammasome-driven pyroptosis in mouse BMDMs and human monocyte-derived macrophages.	Mouse BMDMs Human monocyte-derived macrophages OVA-induced allergic asthma mice Human asthma patients	[34]
		Dectin-1 activated noncanonical caspase-11 inflammasome and triggered pyroptosis, leading to pulmonary neutrophil inflammation in HDM-induced asthmatic mice and MH-S alveolar macrophages. Inhibition of caspase-11 noncanonical inflammasome alleviated Dectin-1-activated airway inflammation, proteolytic activation of GSDMD, and pyroptosis, leading to reduced neutrophil inflammation in HDM-induced asthmatic mice and MH-S alveolar macrophages. Dectin-1 expression in macrophages showed a positive correlation with neutrophil inflammation and caspase-4 expression in asthma patients.	Mouse MH-S cells HDM-induced allergic asthma mice Human asthma patients	[35]
COPD	Caspase-11	Deficiency of caspase-11 noncanonical inflammasome reduced pro-inflammatory cytokine levels in BALF and lung tissues of CS-challenged COPD mice. Deficiency of caspase-11 noncanonical inflammasome alleviated neutrophilia and airway inflammation in BALF and lung tissues of CS-challenged COPD mice.	CS-induced COPD mice	[37]
		Exposure to CS led to alveolar enlargement, collagen deposition, and an increase in mucus and pro-inflammatory cytokine production in mouse lung tissues. Caspase-11 noncanonical inflammasome was activated in lung tissues of CS-exposed mice. CS-induced alveolar enlargement, collagen deposition, and increase in mucus and pro-inflammatory cytokine production were reduced in lung tissues of 129Sv mice, which have nonfunctional caspase-11.	CS-induced COPD mice	[38]
	Caspase-4	The activation of the AIM2 inflammasome triggered the release of IL-1a and TGF-b in exacerbated PBMCs from COPD patients. The release of these two pro-inflammatory cytokines triggered by AIM2 inflammasome activation was dependent on a caspase-4 noncanonical inflammasome.	Human COPD patients	[39]
	Caspase-4/11	M. catarrhalis infection activated caspase-4/11 noncanonical inflammasomes in mouse BMDMs and THP-1 human macrophages. M. catarrhalis infection-induced GSDMD-dependent pyroptosis and NLRP3 canonical inflammasome activation in mouse BMDMs and THP-1 human macrophages	Mouse BMDMs Human THP-1 cells	[41]
ALI & ARDS	Caspase-11	HMGB1 aggravated lung injury and promoted severe inflammation in CLP-induced ALI mice. The expression of HMGB1 and caspase-11 increased in the lungs of CLP-induced ALI mice. Inhibition of HMGB1 decreased expression of caspase-11 and pyroptosis in the lungs of CLP-induced ALI mice.	CLP-induced ALI mice	[45]
		Lung injury and inflammation were diminished in ALI mice lacking HMGB1 and its receptor, RAGE. Lung injury and inflammation were also diminished in ALI mice lacking caspase-11.	CLP-induced ALI mice	[46]
		Luteolin reduced inflammation and lung injury in CLP-induced ALI mice. Levels of caspase-11, GSDMD, and pro-inflammatory cytokines were reduced in the lungs of CLP-induced ALI mice.	CLP-induced ALI mice	[47]
		Caspase-11 noncanonical inflammasome was activated, triggering inflammatory responses in the lungs of LPS-induced ALI mice and primary peritoneal macrophages. Caspase-11 noncanonical inflammasome activation was suppressed in LPS-induced ALI mice lacking CHOP. Caspase-11 noncanonical inflammasome activation was activated in response to an ER stress inducer.	Mouse peritoneal macrophages LPS-induced ALI mice	[48]
		Bhlhe40 was significantly expressed in lung tissues and macrophages of LPS-induced ALI mice. Mice lacking Bhlhe40 exhibited reduced lung tissue damage and inflammatory responses following LPS stimulation. Absence of Bhlhe40 suppressed GSDMD-driven pyroptosis and alleviated lung tissue damage by inhibiting caspase-11 noncanonical inflammasome-activated signaling pathways in LPS-induced ALI mice and macrophages.	Mouse BMDMs RAW264.7 cells LPS-induced ALI mice	[49]
		Plasma ABA levels were elevated in ARDS patients and LPS-induced ALI mice. ABA reduced airway inflammation in ALI mice. ABA suppressed caspase-11 noncanonical inflammasome activation, thereby inhibiting proteolytic activation of GSDMD and preventing GSDMD pore-mediated pyroptosis in alveolar macrophages within the lungs of ALI mice. Protective effect of ABA on LPS-induced pyroptosis in alveolar macrophages was reversed by the overexpression of caspase-11.	Mouse alveolar macrophages LPS-induced ALI mice Human ARDS patients	[50]
	Caspase-4/11	Systemic exposure to LPS triggered severe endothelial pyroptosis, which was mediated by the caspase-4 noncanonical inflammasome in human endothelial cells and the caspase-11 noncanonical inflammasome in LPS-induced ALI mice. In mice lacking caspase-11, bone marrow transplantation with wild-type hematopoietic cells did not prevent LPS-induced ALI. Caspase-11-deficient endothelial cells reduced lung edema, neutrophil accumulation, and mortality caused by LPS-mediated endotoxemia.	hMVECs HPAECs mMVECs LPS-induced ALI mice	[51]
IPF	Caspase-4	IL-1β and IL-18 levels were increased in PBMCs of IPF patients and mice with BLM-induced pulmonary fibrosis. The elevation of these pro-inflammatory cytokines was associated with the release of the pro-fibrotic cytokine TGF-β. AIM2 activation triggered the release of caspase-4 from IPF-derived PBMCs, which corresponded to higher mRNA levels of this caspase in IPF PBMCs compared to healthy ones.	BLM-induced pulmonary fibrosis mice Human IPF patients	[55]
	Caspase-4/11	Levels of caspase-11, cleaved GSDMD, and IL-1β levels were increased, which contributed to pulmonary inflammation in BLM-stimulated human and rat lung epithelial cells, as well as in BLM-induced pulmonary fibrosis mice. Levels of EMT-associated markers were elevated in BLM- stimulated lung epithelial cells and BLM-induced pulmonary fibrosis mice.	Human A549 cells Rat RLE-6TN cells BLM-induced pulmonary fibrosis mice	[56]
		GSDMD-mediated pyroptosis was observed in lung tissues of both silicosis patients and mice. Silica exposure activated the caspase-11 noncanonical inflammasome, leading to IL-1β release and GSDMD-driven pyroptosis in silica-stimulated macrophages.	Mouse peritoneal macrophages Silica-induced silicosis mice Human silicosis patients	[60]