Cholesterol dysregulation and microglial NLRP3 inflammasome activation after ischemic stroke: implications for neuroinflammation and functional recovery
4 affiliations
- 1Department of Cardiology and Cerebrovascular Diseases, Jilin Province Electric Power Hospital
- 2Department of Oncological Neurosurgery, The First Hospital of Jilin University, Xinmin, Changchun
- 3Lingyun Township Health Center, Dongliao, Liaoyuan
- 4Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin, Changchun
Abstract
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–brain 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–STING 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–microglia–NLRP3 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.
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BibTeX
@article{wang2026cholesterol,
title = {{Cholesterol dysregulation and microglial NLRP3 inflammasome activation after ischemic stroke: implications for neuroinflammation and functional recovery}},
author = {Jing Wang and Pingxu An and Chunyan Fu and Xingqi Su and Yan Sun and Di Ma and Xu Shi and Xinyu Hong},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1953192},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1953192/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cholesterol dysregulation and microglial NLRP3 inflammasome activation after ischemic stroke: implications for neuroinflammation and functional recovery
AU - Jing Wang
AU - Pingxu An
AU - Chunyan Fu
AU - Xingqi Su
AU - Yan Sun
AU - Di Ma
AU - Xu Shi
AU - Xinyu Hong
PY - 2026
DA - 2026/10/07
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1953192
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1953192/full
AB - 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–brain 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–STING 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–microglia–NLRP3 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.
SN - 1664-3224
ER -