J Exp Med. 2026 Apr 6;223(4):e20242025. doi: 10.1084/jem.20242025. Epub 2026 Mar 18.
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.
PMID:41848599 | DOI:10.1084/jem.20242025