{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wang C"],"funding":["NIAMS NIH HHS"],"pagination":["eabj3859"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8780201"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6(64)"],"pubmed_abstract":["NOD-like receptor (NLR), family pyrin domain containing 3 (NLRP3) assembles a protein complex known as the NLRP3 inflammasome upon sensing certain pathogen products or sterile danger signals. Gain-of-function mutations such as the D301N substitution in NLRP3, which cause its constitutive activation (NLRP3<sup>CA</sup>) also results in inflammasome assembly. This inflammasome processes pro–interleukin-1 β (pro–IL-1β) and pro–IL-18 into bioactive IL-1β and IL-18, respectively, and cleaves gasdermin D (GSDMD). GSDMD amino-terminal fragments form plasma membrane pores that facilitate the secretion of IL-1β and IL-18 and lead to the inflammatory cell death pyroptosis. Accordingly, GSDMD inactivation results in negligible spontaneous inflammation in various experimental models such as in <i>Nlrp3<sup>CA/+</sup></i> mice lacking GSDMD (<i>Nlrp3<sup>CA/+</sup></i>;<i>Gsdmd<sup>−/−</sup></i> mice). Here, we found that <i>Nlrp3<sup>CA/+</sup></i>;<i>Gsdmd<sup>−/−</sup></i> mice, when challenged with LPS or TNF-α, still secreted IL-1β and IL-18, indicating inflammasome activation independent of GSDMD. Accordingly, <i>Gsdmd<sup>−/−</sup></i> macrophages failed to secrete IL-1β and undergo pyroptosis when briefly exposed to NLRP3 inflammasome activators but released these cytokines when persistently activated. Sustained NLRP3 inflammasome induced caspase-8/-3 and GSDME cleavage and IL-1β maturation in vitro in <i>Gsdmd<sup>−/−</sup></i> macrophages. Thus, a salvage inflammatory pathway involving caspase-8/-3–GSDME was activated after NLRP3 activation when the canonical NLRP3-GSDMD signaling was blocked. Consistent with genetic data, the active metabolite of FDA-approved disulfiram CuET, which inhibited GSDMD and GSDME cleavage in macrophages, reduced the severe inflammation and tissue damage that occurred in the <i>Nlrp3<sup>CA/+</sup></i> mice. Thus, NLRP3 inflammasome activation overwhelms the protection afforded by GSDMD deficiency, rewiring signaling cascades through mechanisms that include GSDME to propagate inflammation."],"journal":["Science immunology"],"pubmed_title":["NLRP3 inflammasome activation triggers gasdermin D-independent inflammation."],"pmcid":["PMC8780201"],"funding_grant_id":["R01 AR076758","R01 AR049192","R01 AR054326","R01 AR068972","R01 AR072623"],"pubmed_authors":["Kanneganti TD","Wang C","Xiao J","Alippe Y","Xu C","Monahan JB","Yang T","Mbalaviele G","Lieberman J","Sun K","Abu-Amer Y"],"additional_accession":[]},"is_claimable":false,"name":"NLRP3 inflammasome activation triggers gasdermin D-independent inflammation.","description":"NOD-like receptor (NLR), family pyrin domain containing 3 (NLRP3) assembles a protein complex known as the NLRP3 inflammasome upon sensing certain pathogen products or sterile danger signals. Gain-of-function mutations such as the D301N substitution in NLRP3, which cause its constitutive activation (NLRP3<sup>CA</sup>) also results in inflammasome assembly. This inflammasome processes pro–interleukin-1 β (pro–IL-1β) and pro–IL-18 into bioactive IL-1β and IL-18, respectively, and cleaves gasdermin D (GSDMD). GSDMD amino-terminal fragments form plasma membrane pores that facilitate the secretion of IL-1β and IL-18 and lead to the inflammatory cell death pyroptosis. Accordingly, GSDMD inactivation results in negligible spontaneous inflammation in various experimental models such as in <i>Nlrp3<sup>CA/+</sup></i> mice lacking GSDMD (<i>Nlrp3<sup>CA/+</sup></i>;<i>Gsdmd<sup>−/−</sup></i> mice). Here, we found that <i>Nlrp3<sup>CA/+</sup></i>;<i>Gsdmd<sup>−/−</sup></i> mice, when challenged with LPS or TNF-α, still secreted IL-1β and IL-18, indicating inflammasome activation independent of GSDMD. Accordingly, <i>Gsdmd<sup>−/−</sup></i> macrophages failed to secrete IL-1β and undergo pyroptosis when briefly exposed to NLRP3 inflammasome activators but released these cytokines when persistently activated. Sustained NLRP3 inflammasome induced caspase-8/-3 and GSDME cleavage and IL-1β maturation in vitro in <i>Gsdmd<sup>−/−</sup></i> macrophages. Thus, a salvage inflammatory pathway involving caspase-8/-3–GSDME was activated after NLRP3 activation when the canonical NLRP3-GSDMD signaling was blocked. Consistent with genetic data, the active metabolite of FDA-approved disulfiram CuET, which inhibited GSDMD and GSDME cleavage in macrophages, reduced the severe inflammation and tissue damage that occurred in the <i>Nlrp3<sup>CA/+</sup></i> mice. Thus, NLRP3 inflammasome activation overwhelms the protection afforded by GSDMD deficiency, rewiring signaling cascades through mechanisms that include GSDME to propagate inflammation.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Oct","modification":"2025-04-18T16:34:17.729Z","creation":"2025-04-07T03:50:20.759Z"},"accession":"S-EPMC8780201","cross_references":{"pubmed":["34678046"],"doi":["10.1126/sciimmunol.abj3859"]}}