Authors
Jinglong Hu, Meijuan Zhang, Pinyi Liu, Yanting Chen, Hailan Meng, Shengnan Xia, Xinyu Bao, Yun Xu, Yan Chen
Published in
Glia. Volume 74. Issue 11. Pages e70215.
Abstract
Microglia are central mediators of neuroinflammation following ischemic stroke. Our previous multi-omics data revealed significant upregulation of leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4) in microglia after transient middle cerebral artery occlusion (tMCAO), but its functional role remains unclear. This study demonstrates that LILRB4 expression peaks at 3 days post-tMCAO and is predominantly localized to microglia. Microglia-specific Lilrb4 knockout (Lilrb4-cKO) displayed worse neurological functions, larger infarct volumes, and more significant microglial activation. Transcriptomic analysis in vitro and functional experiments further revealed that microglial LILRB4 knockdown promoted the release of proinflammatory factors and enhanced necroptosis. Mechanistically, deletion of LILRB4 mainly drives receptor-interacting protein 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) expression and phosphorylation, without affecting receptor-interacting protein 1 (RIPK1). Pharmacologic inhibition of RIPK3 can relieve the brain damage caused by LILRB4 knockout after stroke. Additional analysis showed that LILRB4 negatively regulates the stimulator of interferon genes (STING)/RIPK3 axis to limit microglial necroptosis. STING suppression blocked the hyperactivation of RIPK3 induced by LILRB4 deficiency. In conclusion, LILRB4 attenuates ischemic brain injury by suppressing STING/RIPK3-mediated microglial necroptosis and neuroinflammation, emphasizing its significance as a potential neuroprotective therapy.
PMID:
42678380
Bibliographic data and abstract were imported from PubMed on 01 Sep 2026.
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