Htr2b Enhances the Phagocytosis of Brain Macrophages and Alleviates Brain Injury after Stroke

ABSTRACT: Brain myeloid cells, including infiltrating monocyte-derived macrophages (MDMs) and resident microglia play critical roles in regulating debris clearance following ischemic brain injury, shaping neuroinflammation evolution and neurological outcome, yet the underlying mechanism remains elusive. In this study, using single-cell RNA sequencing and fate mapping, we identified serotonin receptor Htr2b+ MDMs as a pivotal subgroup involved in resolving neuroinflammation within the ischemic penumbra. In addition, we find significant accumulation of Htr2b+ MDMs with enhanced phagocytosis and inflammation-resolving gene signatures in the peri-infarct region. Mechanistically, Htr2b activation promotes nuclear translocation of Tfe3, a key lysosomal regulator, enhancing lysosomal biogenesis and supporting sustained phagocytic activity. Myeloid-specific Htr2b ablation impairs debris clearance, exacerbates neuroinflammation and ischemic injury, while pharmacological Htr2b agonism or Tfe3 activation restores the lysosomal competence of brain MDMs and improves post-stroke neurological outcome. In conclusion, we demonstrate a novel Htr2b+ MDM subset that integrates serotonin signaling to license their intrinsic phagocytosis function, alleviating ischemic brain injury.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: yonghui chen  

LAB HEAD: Yueman zhang

PROVIDER: PXD074993 | Pride | 2026-07-04

REPOSITORIES: Pride