Related Experiment Video
Updated: Mar 19, 2026
Isolation and Flow Cytometric Assessment of Neuroimmune Interactions in a Mini-Stroke Murine Model
Published on: June 20, 2025
Hypoxia-inducible protein 2 mediates metabolic adaptation of Ly6ChighLy6Glow monocytes after stroke
Weijie Chen1,2, Xin Wang1,2, Tingting Huang1,2
1Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Ly6Chigh monocytes, previously recognized as a pro-inflammatory subset, play critical roles in secondary neuroinflammation in the stroke brain. Growing evidence reveals increased infiltration of myeloid cells with substantial heterogeneity, raising the question of how Ly6Chigh monocyte-derived macrophages in the stroke brain adapt to the ischemic environment. Here, by combining analysis of stroke patient samples with in vivo and in vitro murine studies and single-cell transcriptomic profiling, we identify hypoxia-inducible lipid droplet-associated protein (Hilpda)/hypoxia-inducible protein 2 (HIG2) as a critical mediator of anti-inflammatory property of Ly6ChighLy6Glow monocyte-derived macrophages in the stroke brain. Mechanistically, HIG2 promotes phosphatidylcholine synthesis via Hif1α-dependent transcriptional regulation of choline kinase α, initiating lipid metabolism reprogramming that underpins the anti-inflammatory phenotype of Ly6ChighLy6Glow monocyte-derived macrophages in the ischemic brain after stroke. Intranasal delivery of recombinant HIG2 protein improves neurological outcomes after stroke. These findings suggest that targeting HIG2 might represent a novel immunometabolic strategy to mitigate poststroke neuroinflammation.
Insights
Hypoxia-inducible protein 2 (HIG2) helps Ly6ChighLy6Glow monocyte-derived macrophages become anti-inflammatory in stroke brains. Targeting HIG2 may offer new ways to reduce neuroinflammation after stroke.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Ly6Chigh monocytes are pro-inflammatory and crucial in stroke-induced neuroinflammation.
- Myeloid cell infiltration in stroke brains is heterogeneous, prompting investigation into monocyte-derived macrophage adaptation.
- Understanding these adaptations is key to developing effective stroke therapies.
Purpose of the Study:
- To identify mechanisms underlying the anti-inflammatory properties of Ly6ChighLy6Glow monocyte-derived macrophages in the ischemic stroke brain.
- To explore the role of hypoxia-inducible lipid droplet-associated protein (Hilpda)/hypoxia-inducible protein 2 (HIG2) in this process.
- To evaluate HIG2 as a potential therapeutic target for post-stroke neuroinflammation.
Main Methods:
- Combined analysis of human stroke patient samples with in vivo and in vitro murine models.
- Single-cell transcriptomic profiling to analyze myeloid cell populations.
- Investigated the role of HIG2 in lipid metabolism and inflammatory signaling pathways.
Main Results:
- Identified HIG2 as a critical mediator of the anti-inflammatory phenotype in Ly6ChighLy6Glow monocyte-derived macrophages.
- Demonstrated that HIG2 promotes phosphatidylcholine synthesis via Hif1α-dependent regulation of choline kinase α.
- Showed that intranasal delivery of recombinant HIG2 protein improved neurological outcomes in murine stroke models.
Conclusions:
- HIG2 orchestrates lipid metabolism reprogramming, conferring anti-inflammatory properties to specific monocyte-derived macrophages in the ischemic brain.
- Targeting HIG2 represents a promising novel immunometabolic strategy for mitigating post-stroke neuroinflammation.
- HIG2's role highlights the potential of targeting metabolic pathways for neurological recovery.
