NLRP3 Inflammasome Deficiency Protects against Microbial Sepsis via Increased Lipoxin B₄Synthesis

Abstract

Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7-dependent repression of LXB biosynthesis, and increased survival potentially via LXB production and inhibition of proinflammatory cytokines.

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

“…Our evidence demonstrates a complete lipoxin synthetic and signaling circuit in astrocytes and the inner retina, while ALX/FPR2 inhibition suggests that LXA 4 signaling plays a role in acute injury. In comparison, the formation and bioactions of LXB 4 have not been fully investigated, but it has been shown to block TNF-α secretion by activated T cells (51), and its production is regulated by NLRP3 inflammasome activity (52). We observed that inhibition of the LXA 4 receptor (ALX/FPR2) or RvD2 receptor (GPR18) was insufficient to block protective LXB 4 activity.…”

“…Analysis was carried out in negative ion mode, and eicosanoids and PUFA were quantitated using scheduled multiple reaction monitoring (MRM) using from 4 to 6 specific transition ions for each analyte. We used specific retention time and established prominent fragment ions for identification and quantification of LXB 4 and LXA 4 (52,71,72 qPCR. Mouse retinal mRNA was isolated using RNeasy Isolation Kit (QIAGEN), quantified using NanoDrop, and mRNA reverse transcribed with the High Capacity cDNA Kit (Applied Biosystems).…”

Oxidative lipidomics: applications in critical care

“…These results shows the importance of SPMs in treating sepsis [34*]. In a different set of experiments with a similar sepsis model, NLRP3 inflammasome deficiency protected against sepsis by downregulating pro-inflammatory lipid mediators and upregulating SPMs, particularly through the increased synthesis of the arachidonic acid-derived lipid mediator, lipoxin B4 [35*]. Along these lines, a lipid mediator study in medical ICU patients with sepsis showed higher pro- inflammatory mediators such as prostaglandin F2α and leukotriene B4 in non-survivors and higher proresolving mediators such as resolvin E1, resolvin D5, and 17R-protectin D1 in survivors [36**].…”

Integrating molecular pathogenesis and clinical translation in sepsis-induced acute respiratory distress syndrome

“…Inflammasomes are multiprotein complexes that mediate caspase-1 activation, which promotes maturation and secretion of IL-1β and IL-18. Interestingly, mice lacking key autophagy proteins produced higher levels of IL-1β and IL-18 in sepsis models and had higher LPS-and polymicrobial sepsis-induced mortality than WT controls (51)(52)(53).…”