biostudies-literatureFrising UCFonds Wetenschappelijk OnderzoekBijzonder Onderzoeksfonds UGente54339https://www.ebi.ac.uk/biostudies/studies/S-EPMC9253760biostudies-literatureUnknown23(7)Cryopyrin-associated periodic syndromes (CAPS) are a spectrum of autoinflammatory disorders caused by gain-of-function NLRP3 mutant proteins that form hyperactive inflammasomes leading to overproduction of the pro-inflammatory cytokines IL-1β and IL-18. Expressing the murine gain-of-function Nlrp3^A350V mutant selectively in neutrophils recapitulates several autoinflammatory features of human CAPS, but the potential contribution of macrophage inflammasome hyperactivation to CAPS development is poorly defined. Here, we show that expressing Nlrp3^A350V in macrophages is sufficient for driving severe multi-organ autoinflammation leading to perinatal lethality in mice. In addition, we show that macrophages contribute to autoinflammation also in adult mice, as depleting macrEMBO reportsNlrp3 inflammasome activation in macrophages suffices for inducing autoinflammation in mice.PMC92537603G.0448.18G.0C49.13NBOF24Y20190032013G.0447.18FWOOPR2018010801Frising UCDoglio MGWullaert ARibo Svan Loo GMalissen BfalseNlrp3 inflammasome activation in macrophages suffices for inducing autoinflammation in mice.Cryopyrin-associated periodic syndromes (CAPS) are a spectrum of autoinflammatory disorders caused by gain-of-function NLRP3 mutant proteins that form hyperactive inflammasomes leading to overproduction of the pro-inflammatory cytokines IL-1β and IL-18. Expressing the murine gain-of-function Nlrp3^A350V mutant selectively in neutrophils recapitulates several autoinflammatory features of human CAPS, but the potential contribution of macrophage inflammasome hyperactivation to CAPS development is poorly defined. Here, we show that expressing Nlrp3^A350V in macrophages is sufficient for driving severe multi-organ autoinflammation leading to perinatal lethality in mice. In addition, we show that macrophages contribute to autoinflammation also in adult mice, as depleting macr2022-01-01T00:00:00Z2022 Jul2025-04-19T02:39:01.832Z2025-04-07T13:01:57.901ZS-EPMC92537603557499410.15252/embr.202154339