{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T16:48:03Z","timestamp":1793378883713,"version":"4.5.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aimed to investigate the role and underlying mechanism of DJ-1 in regulating NLRP3 inflammasome-mediated neuroinflammation during Parkinson\u2019s disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used LPS to stimulate primary microglia <jats:italic>in vitro<\/jats:italic> and performed stereotactic injection of LPS into the substantia nigra of mice <jats:italic>in vivo<\/jats:italic> to investigate changes in DJ-1 expression following inflammatory stimulation. To evaluate the functional effects of DJ-1 on NLRP3 inflammasome activation, we used siRNA to knock down DJ-1 in primary microglia or BMDMs and analyzed downstream inflammatory responses as well as the specificity of this regulation. <jats:italic>In vivo<\/jats:italic>, we used microglia-specific AAV to selectively silence DJ-1 in the substantia nigra to further evaluate the anti-inflammatory effect of DJ-1 deficiency. To validate the direct interaction between DJ-1 and NLRP3, we performed co-immunoprecipitation and proximity ligation assay. We used the autophagy inhibitor 3-MA and activator rapamycin to investigate how NLRP3 is degraded upon DJ-1 deficiency in CRISPR-Cas9-engineered DJ-1 knockout HEK-293 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DJ-1 were significantly upregulated following LPS or LPS plus ATP stimulation in primary microglia. Similarly, after stereotactic LPS injection into the substantia nigra, we observed a significant upregulation of DJ-1 expression. Knockdown of microglial DJ-1 markedly suppressed NLRP3 inflammasome activation, as evidenced by reduced mature caspase-1 and decreased IL-1\u03b2 secretion. We confirmed this phenomenon in BMDM and found that DJ-1 knockdown specifically inhibited NLRP3 inflammasome activation, with no effect on NLRC4 or AIM2 inflammasomes. <jats:italic>In vivo<\/jats:italic>, microglia-specific DJ-1 knockdown significantly attenuated microglial NLRP3 inflammasome activation in the substantia nigra and exerted neuroprotective effects after LPS treatment. Furthermore, DJ-1 was found to directly bind NLRP3 and stabilize its conformation, thereby preventing autophagic degradation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study demonstrates that DJ-1 deficiency in microglia inhibits NLRP3-driven inflammation by promoting NLRP3 degradation through the autophagy-lysosome pathway. Future studies should focus on identifying the specific binding sites and structure of DJ-1 with NLRP3, as well as investigating whether inhibiting DJ-1 in microglia could serve as a potential therapeutic target for suppressing neuroinflammation in Parkinson\u2019s disease.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1656729","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T04:11:23Z","timestamp":1757304683000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Loss of DJ-1 alleviates microglia-mediated neuroinflammation in Parkinson\u2019s disease via autophagy-lysosomal degradation of 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