{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:17:03Z","timestamp":1787613423263,"version":"build-2736575974"},"reference-count":55,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T00:00:00Z","timestamp":1746662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["DM190884"],"award-info":[{"award-number":["DM190884"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["C39071GG"],"award-info":[{"award-number":["C39071GG"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["175153"],"award-info":[{"award-number":["175153"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004856","name":"New York State Department of Health","doi-asserted-by":"publisher","award":["DM190884"],"award-info":[{"award-number":["DM190884"]}],"id":[{"id":"10.13039\/100004856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004856","name":"New York State Department of Health","doi-asserted-by":"publisher","award":["C39071GG"],"award-info":[{"award-number":["C39071GG"]}],"id":[{"id":"10.13039\/100004856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004856","name":"New York State Department of Health","doi-asserted-by":"publisher","award":["175153"],"award-info":[{"award-number":["175153"]}],"id":[{"id":"10.13039\/100004856","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Trauma Research and Combat Casualty Care Collaborative","award":["DM190884"],"award-info":[{"award-number":["DM190884"]}]},{"name":"The Trauma Research and Combat Casualty Care Collaborative","award":["C39071GG"],"award-info":[{"award-number":["C39071GG"]}]},{"name":"The Trauma Research and Combat Casualty Care Collaborative","award":["175153"],"award-info":[{"award-number":["175153"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cell death and inflammation are key innate immune responses, but excessive activation can cause tissue damage. The NLRP3 inflammasome is a promising target for reducing inflammation and promoting recovery. Immunometabolism regulates NLRP3 responses in neurological and inflammatory diseases through cyclic nucleotide signaling. Targeting phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, offer a novel approach to mitigate inflammation. While 14 PDE inhibitors are FDA-approved, PDE10A\u2019s role in NLRP3 inflammasome activation remains unclear. This study investigates the effects of PDE10A inhibition on inflammasome-driven inflammation using two PDE10A inhibitors, MP-10 and TP-10, in macrophage and animal models of sepsis and traumatic nerve injury. Our results show that PDE10A inhibition reduces inflammasome activation by preventing ASC speck formation and by lowering levels of cleaved caspase-1, gasdermin D, and IL-1\u03b2, which are key mediators of pyroptosis. In the sepsis model, MP-10 significantly reduced inflammation, decreased plasma IL-1\u03b2, alleviated thrombocytopenia, and improved organ damage markers. In the nerve injury model, PDE10A inhibition enhanced motor function recovery and reduced muscle atrophy-related gene expression. These findings suggest that PDE10A inhibition could be a promising therapeutic approach for inflammatory and neuromuscular injuries. Given MP-10\u2019s established safety in human trials, Phase 2 clinical studies for sepsis and nerve injury are highly promising.<\/jats:p>","DOI":"10.3390\/ijms26104498","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T11:37:02Z","timestamp":1746704222000},"page":"4498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["PDE10A Inhibition Reduces NLRP3 Activation and Pyroptosis in Sepsis and Nerve Injury"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-4115","authenticated-orcid":false,"given":"Bradford C.","family":"Berk","sequence":"first","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila Lage","family":"Ch\u00e1vez","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1133-4116","authenticated-orcid":false,"given":"Chia","family":"George Hsu","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, The University of Texas at San Antonio, San Antonio, TX 78249, USA"},{"name":"Department of Molecular Microbiology and Immunology, The University of Texas at San Antonio, San Antonio, TX 78249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/s41586-024-07873-4","article-title":"Fibrin drives thromboinflammation and neuropathology in COVID-19","volume":"633","author":"Ryu","year":"2024","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1186\/s12974-016-0736-y","article-title":"Multiple organ dysfunction and systemic inflammation after spinal cord injury: A complex relationship","volume":"13","author":"Sun","year":"2016","journal-title":"J. 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