Editors' ChoiceInflammation

PAF and the inflammasome

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Science Signaling  08 Oct 2019:
Vol. 12, Issue 602, eaaz7370
DOI: 10.1126/scisignal.aaz7370

The phospholipid PAF stimulates NLRP3 inflammasome activation and inflammatory cytokine production independently of its GPCR.

Platelet-activating factor (PAF) is a phospholipid that stimulates platelet aggregation by binding to its cognate G protein–coupled receptor (GPCR), PAFR, which also binds to the PAF derivative lysoPAF. However, PAFR is found on many cell types, and PAF is also implicated in mediating various inflammatory disorders. Noting that PAFR antagonists as treatments for asthma and sepsis have failed in clinical trials, Deng et al. sought alternative mechanisms by which PAF could drive inflammation. They showed that PAF induced the production of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 by mouse and human myeloid cells that had first been primed with the microbial product lipopolysaccharide (LPS). Imaging and Western blotting analyses showed that PAF specifically induced the assembly and activation of a cytosolic, multiprotein complex known as the NLRP3 inflammasome, which resulted in activation of the enzyme caspase-1 and processing of the proforms of IL-1β and IL-18. PAF-induced cytokine production by myeloid cells depended on the NLRP3-associated kinase NEK7 and was blocked by an NLRP3-specific inhibitor. Although PAF stimulated the processing of the protein gasdermin-D (GSDMD) in LPS-primed myeloid cells, which is characteristic of other NLRP3 activators, the pore-forming cleavage product of GSDMD was not required for PAF-induced cytokine release. In vitro experiments showed that PAF-induced IL-1β production was not blocked by PAFR antagonists or by knockout of Pafr. Intraperitoneal priming of mice with LPS followed by challenge with lysoPAF resulted in increased serum concentrations of IL-1β, recruitment of neutrophils, and peritonitis, all of which were inhibited when lysoPAF was administered together with an NLRP3 antagonist. Experiments with specific knockout mice showed that PAF-induced inflammation required NLRP3 but was independent of PAFR. Together, these data provide evidence of the activation of the NLPR3 inflammasome by a phospholipid and suggest a PAFR-independent mechanism for PAF-induced inflammation.

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