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Immunol."],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic coronavirus to emerge in humans in recent decades. Although primarily a respiratory virus, SARS-CoV-2 can invade the central nervous system (CNS), leading to severe neurological manifestations such as stroke, encephalopathy, and memory loss. However, the mechanisms by which neural cells control SARS-CoV-2 infection remain poorly understood. Here, we demonstrate that SARS-CoV-2 and its Nucleocapsid (N) and Spike (S) proteins induce classical NLRP3 inflammasome activation in astrocytes. Notably, astrocytes lacking NLRP3 or caspase-1 exhibit higher viral loads, indicating a crucial role of the NLRP3 inflammasome in astrocyte-mediated viral control. Similarly, gasdermin-D (GSDMD)-deficient astrocytes display increased susceptibility to infection, although their LDH release remains unaffected, suggesting that pyroptosis is not required for viral restriction. Instead, GSDMD deficiency leads to markedly reduced IL-1\u03b2 secretion, and exogenous IL-1\u03b2 rescues the impaired antiviral response in NLRP3-, caspase-1-, and GSDMD-deficient astrocytes. Our findings reveal that astrocytes autonomously control SARS-CoV-2 infection via the NLRP3-GSDMD-IL-1\u03b2 axis, underscoring their active role in the neuroimmune response to viral infection.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1703765","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T06:29:24Z","timestamp":1768890564000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["NLRP3 inflammasome activation in astrocytes restricts SARS-CoV-2 through gasdermin-D-driven IL-1\u03b2 release"],"prefix":"10.3389","volume":"16","author":[{"given":"Ingrid S.","family":"de Farias","sequence":"first","affiliation":[{"name":"Departamento de Farmacologia, Escola Paulista de Medicina\/Universidade Federal de S\u00e3o Paulo (EPM\/UNIFESP)","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Programa de p\u00f3s-gradua\u00e7\u00e3o em Imunologia, Instituto de Ci\u00eancias Biom\u00e9dicas, 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Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria Weise L.","family":"de Lucena","sequence":"additional","affiliation":[{"name":"Departamento de Farmacologia, Escola Paulista de Medicina\/Universidade Federal de S\u00e3o Paulo (EPM\/UNIFESP)","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana T.","family":"Maricato","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Imunologia, Parasitologia, Escola Paulista de Medicina\/Universidade Federal de S\u00e3o Paulo (EPM\/UNIFESP)","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo T.","family":"Gazzinelli","sequence":"additional","affiliation":[{"name":"Centro de Tecnologia em Vacinas, Universidade Federal de Minas Gerais","place":["Belo Horizonte, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luiz M\u00e1rio 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