Fig. 2.

Mechanisms of immunometabolism during ALI. Undesirable stimulus such as LPS, SARS-CoV-2, and hypoxia could activate toll-like and TNF-α receptors, subsequently transcriptionally activating IL-1β, IL-18, NLRP3, and HIF-1α in a NF-κb dependent manner. PKM2-dependent glycolysis triggers LPS-induced inflammatory responses of macrophages and aggravated ALI by activating NLRP3 inflammasome. Dimeric PKM2 could interact with HIF-1α, thus activating glycolysis. Bacterial NAG could bind to and inhibit HK activity, giving rise to the dissociation of HK from VDACs and in turn release mitochondrial DNA to activate NLRP3 inflammasome. Aberrantmitochondrial homeostasis also gives rise to the accumulation of the TCA, which could derivative both succinate and itaconate. Succinate and itaconate exert opposite effects on NLRP3 inflammasome activation. Reduced NAD⁺ availability could inhibit SIRT1/2/3, thus activating NLRP3 inflammasome.