{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:52:29Z","timestamp":1791363149702,"version":"4.3.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"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:p>Secondary neuroinflammation is an important determinant of tissue injury, repair, and neurological recovery after ischemic stroke, yet the lipid-metabolic environment in which this response develops remains incompletely integrated into current mechanistic models. This narrative review synthesizes PubMed-indexed, peer-reviewed literature published between 2010 and 2026 on post-stroke cholesterol metabolism, microglial lipid handling, NLRP3 inflammasome signaling, immunometabolic remodeling, therapeutic intervention, and recovery-related outcomes. Ischemic injury substantially remodels the local lipid environment through neuronal membrane disruption, myelin breakdown, oxidative lipid modification, altered cholesterol turnover, and blood\u2013brain barrier dysfunction, generating a heterogeneous pool of free cholesterol, cholesteryl esters, lipid droplets, cholesterol crystals, oxysterols, and oxidized lipids. Stroke-specific studies increasingly support the emergence of cholesterol- and lipid-loaded microglial states and show that microglial lipid-processing capacity, including TREM2- and SREBP2-related mechanisms, can influence inflammatory and reparative responses. However, the causal connection between cholesterol dysregulation and NLRP3 activation remains only partly resolved. Direct stroke evidence supports the coexistence of microglial cholesterol overload and NLRP3-associated inflammatory changes, whereas detailed mechanisms involving cholesterol crystal-induced lysosomal injury, metabolic remodeling, and intracellular lipid stress remain partly dependent on cross-model evidence. Oxysterol effects are context dependent, and recent cholesterol-mobilization experiments identify mitochondrial DNA leakage\u2013STING signaling as an alternative, more directly validated downstream pathway. Post-stroke microglia are also functionally heterogeneous, with distinct populations contributing to debris clearance, white matter repair, and neurological recovery. Therapeutically, systemic lipid management should be distinguished from experimental strategies that modify brain cholesterol handling or suppress inflammasome-associated inflammation, and no integrated cholesterol\u2013microglia\u2013NLRP3 treatment strategy has yet been clinically validated. Collectively, current evidence supports a proposed, evidence-stratified framework in which cholesterol-related lipid stress, microglial state, inflammasome susceptibility, and tissue repair partially converge rather than forming a single validated linear causal axis.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1953192","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:25:51Z","timestamp":1791361551000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cholesterol dysregulation and microglial NLRP3 inflammasome activation after ischemic stroke: implications for neuroinflammation and functional recovery"],"prefix":"10.3389","volume":"17","author":[{"given":"Jing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology and Cerebrovascular Diseases, Jilin Province Electric Power Hospital","place":["Shuxun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingxu","family":"An","sequence":"additional","affiliation":[{"name":"Department of Oncological Neurosurgery, The First Hospital of Jilin University, Xinmin, Changchun","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Fu","sequence":"additional","affiliation":[{"name":"Lingyun Township Health Center, Dongliao, Liaoyuan","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingqi","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin, Changchun","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Cerebrovascular Diseases, Jilin Province Electric Power Hospital","place":["Shuxun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin, Changchun","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Cerebrovascular Diseases, Jilin Province Electric Power Hospital","place":["Shuxun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Oncological Neurosurgery, The First Hospital of Jilin University, Xinmin, Changchun","place":["Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.122.036946","article-title":"Neuroinflammation, stroke, blood-brain barrier dysfunction, and imaging modalities","volume":"53","author":"Candelario-Jalil","year":"2022","journal-title":"Stroke"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.980722","article-title":"Microglia-mediated neuroinflammation and neuroplasticity after stroke","volume":"16","author":"Wang","year":"2022","journal-title":"Front Cell Neurosci"},{"key":"B3","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3390\/ijms23010014","article-title":"Neuroinflammation in cerebral ischemia and ischemia\/reperfusion injuries: From pathophysiology to therapeutic strategies","volume":"23","author":"Jurcau","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110332","article-title":"Neuroinflammation and peripheral immunity: Focus on ischemic stroke","volume":"120","author":"Wang","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.3390\/ph15101168","article-title":"Molecular mechanisms of inflammasome in ischemic stroke pathogenesis","volume":"15","author":"Puleo","year":"2022","journal-title":"Pharm (Basel)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2023.114578","article-title":"Nlrp3 inflammasome activation after ischemic stroke","volume":"452","author":"Han","year":"2023","journal-title":"Behav Brain Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s13105-021-00817-w","article-title":"Pyroptosis in stroke-new insights into disease mechanisms and therapeutic strategies","volume":"77","author":"Gou","year":"2021","journal-title":"J Physiol Biochem"},{"key":"B8","doi-asserted-by":"publisher","first-page":"139","DOI":"10.3892\/ijmm.2025.5580","article-title":"Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (review)","volume":"56","author":"Sun","year":"2025","journal-title":"Int J Mol Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.568641","article-title":"Effects of Cyp46a1 inhibition on long-term-depression in hippocampal slices ex vivo and 24s-hydroxycholesterol levels in mice in vivo","volume":"13","author":"Popiolek","year":"2020","journal-title":"Front Mol Neurosci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-025-01379-7","article-title":"Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke","volume":"7","author":"Zhao","year":"2025","journal-title":"Nat Metab"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202306863","article-title":"Dynamic brain lipid profiles modulate microglial lipid droplet accumulation and inflammation under ischemic conditions in mice","volume":"11","author":"Wei","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.18632\/aging.203337","article-title":"25-hydroxycholesterol protecting from cerebral ischemia-reperfusion injury through the inhibition of sting activity","volume":"13","author":"Lin","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nature08938","article-title":"Nlrp3 inflammasomes are required for atherogenesis and activated by cholesterol crystals","volume":"464","author":"Duewell","year":"2010","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/cns.71073","article-title":"Cholesterol drives ifitm3(+) microglia activation and induces sting mediated neuroinflammation after ischemic stroke","volume":"32","author":"Cheng","year":"2026","journal-title":"CNS Neurosci Ther"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-025-01526-w","article-title":"Microglial-derived cholesterol 25-hydroxylase promotes epileptic seizure and neuroinflammation mediated by nlrp3 inflammasome and lipid metabolism","volume":"42","author":"Zhang","year":"2026","journal-title":"Neurosci Bull"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/srep09144","article-title":"7-ketocholesterol increases retinal microglial migration, activation, and angiogenicity: A potential pathogenic mechanism underlying age-related macular degeneration","volume":"5","author":"Indaram","year":"2015","journal-title":"Sci Rep"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100985","article-title":"7-ketocholesterol-induced inflammation signals mostly through the tlr4 receptor both in vitro and in vivo","volume":"9","author":"Huang","year":"2014","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2023.117229","article-title":"Hdl cholesterol efflux capacity and phospholipid content are associated with the severity of acute ischemic stroke and predict its outcome","volume":"540","author":"Papagiannis","year":"2023","journal-title":"Clin Chim Acta"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1177\/0271678x251327944","article-title":"Elucidating stroke etiology through lipidomics of thrombi and plasma in acute ischemic stroke patients undergoing endovascular thrombectomy","volume":"46","author":"Cheng","year":"2026","journal-title":"J Cereb Blood Flow Metab"},{"key":"B20","doi-asserted-by":"publisher","first-page":"3089","DOI":"10.1038\/s41467-025-58254-y","article-title":"Repair-associated macrophages increase after early-phase microglia attenuation to promote ischemic stroke recovery","volume":"16","author":"Zhang","year":"2025","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2639","article-title":"Cd36 coordinates nlrp3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation","volume":"14","author":"Sheedy","year":"2013","journal-title":"Nat Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115962","article-title":"Trem2 regulates microglial lipid droplet formation and represses post-ischemic brain injury","volume":"170","author":"Wei","year":"2024","journal-title":"BioMed Pharmacother"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.10.012","article-title":"Sphingosine-1-phosphate, a novel trem2 ligand, promotes microglial phagocytosis to protect against ischemic brain injury","volume":"12","author":"Xue","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"B24","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.freeradbiomed.2026.08.008","article-title":"Microglial srebp2 regulate cholesterol-related lipid metabolism and inflammatory levels following ischemic stroke via the autophagy pathway","volume":"255","author":"Wei","year":"2026","journal-title":"Free Radic Biol Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01711-x","article-title":"Analysis of brain and blood single-cell transcriptomics in acute and subacute phases after experimental stroke","volume":"25","author":"Garcia-Bonilla","year":"2024","journal-title":"Nat Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg1323","article-title":"Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain","volume":"16","author":"Han","year":"2024","journal-title":"Sci Transl Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"6232","DOI":"10.1038\/s41467-024-50465-z","article-title":"Single-nucleus rna sequencing reveals glial cell type-specific responses to ischemic stroke in male rodents","volume":"15","author":"Bormann","year":"2024","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s13073-021-00863-5","article-title":"Microglial pgc-1\u03b1 protects against ischemic brain injury by suppressing neuroinflammation","volume":"13","author":"Han","year":"2021","journal-title":"Genome Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/s41419-025-08114-w","article-title":"Metabolic reprogramming in ischemic stroke: When glycolytic overdrive meets lipid storm","volume":"16","author":"Wang","year":"2025","journal-title":"Cell Death Dis"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250684","article-title":"Mtor- and hif-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13280","article-title":"Pkm2-dependent glycolysis promotes nlrp3 and aim2 inflammasome activation","volume":"7","author":"Xie","year":"2016","journal-title":"Nat Commun"},{"key":"B32","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/s41420-025-02453-5","article-title":"Pkm2-mediated metabolic reprogramming of microglia in neuroinflammation","volume":"11","author":"Zhang","year":"2025","journal-title":"Cell Death Discov"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2024.100534","article-title":"Cholesterol trafficking to the er leads to the activation of camkii\/jnk\/nlrp3 and promotes atherosclerosis","volume":"65","author":"Yalcinkaya","year":"2024","journal-title":"J Lipid Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nature16959","article-title":"Nek7 is an essential mediator of nlrp3 activation downstream of potassium efflux","volume":"530","author":"He","year":"2016","journal-title":"Nature"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1295-z","article-title":"Structural mechanism for nek7-licensed activation of nlrp3 inflammasome","volume":"570","author":"Sharif","year":"2019","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","first-page":"74","DOI":"10.3892\/ijmm.2022.5130","article-title":"Focus on the role of mitochondria in nlrp3 inflammasome activation: A prospective target for the treatment of ischemic stroke (review)","volume":"49","author":"Zhang","year":"2022","journal-title":"Int J Mol Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s12974-023-02799-6","article-title":"Novel ch25h(+) and oasl(+) microglia subclusters play distinct roles in cerebral ischemic stroke","volume":"20","author":"Zhang","year":"2023","journal-title":"J Neuroinflamm"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13129","article-title":"25-hydroxycholesterol contributes to cerebral inflammation of x-linked adrenoleukodystrophy through activation of the nlrp3 inflammasome","volume":"7","author":"Jang","year":"2016","journal-title":"Nat Commun"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.714943","article-title":"Janus kinase inhibition ameliorates ischemic stroke injury and neuroinflammation through reducing nlrp3 inflammasome activation via jak2\/stat3 pathway inhibition","volume":"12","author":"Zhu","year":"2021","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1016\/j.immuni.2021.04.022","article-title":"Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke","volume":"54","author":"Shi","year":"2021","journal-title":"Immunity"},{"key":"B41","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41419-023-05689-0","article-title":"Cd11c(+) microglia promote white matter repair after ischemic stroke","volume":"14","author":"Jia","year":"2023","journal-title":"Cell Death Dis"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.01.035","article-title":"Nlrp3 inflammasome inhibition with mcc950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia","volume":"142","author":"Ward","year":"2019","journal-title":"Pharmacol Res"},{"key":"B43","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s12974-023-02741-w","article-title":"Trem2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair","volume":"20","author":"Xu","year":"2023","journal-title":"J Neuroinflamm"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1161\/str.0000000000000375","article-title":"2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline from the American Heart Association\/American Stroke Association","volume":"52","author":"Kleindorfer","year":"2021","journal-title":"Stroke"},{"key":"B45","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1124\/pharmrev.120.000171","article-title":"Pharmacological inhibition of the nod-like receptor family pyrin domain containing 3 inflammasome with mcc950","volume":"73","author":"Corcoran","year":"2021","journal-title":"Pharmacol Rev"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2021.113952","article-title":"Exercise-induced neuroprotection against cerebral ischemia\/reperfusion injury is mediated via alleviating inflammasome-induced pyroptosis","volume":"349","author":"Liu","year":"2022","journal-title":"Exp Neurol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202311803","article-title":"Neutrophil membrane-camouflaged polyprodrug nanomedicine for inflammation suppression in ischemic stroke therapy","volume":"36","author":"Zhao","year":"2024","journal-title":"Adv Mater"},{"key":"B48","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1186\/s12951-025-03540-6","article-title":"Brain targeted lipid nanoparticles with hv1 inhibitors alleviate neuroinflammation post-ischemic stroke","volume":"23","author":"Yang","year":"2025","journal-title":"J Nanobiotechnol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1953192\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:25:52Z","timestamp":1791361552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1953192\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2026.1953192"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1953192","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]},"article-number":"1953192"}}