Serotonin signaling enhances phagocytosis by brain macrophages through Htr2b and alleviates brain injury after stroke.

Htr2b+ infiltrating monocyte-derived macrophages in the ischemic penumbra significantly accumulate and show enhanced phagocytosis, linked to improved inflammation resolution after stroke.

• Why it matters: Brain myeloid cells help clear debris and shape neuroinflammation after ischemia, but the serotonin-linked mechanisms that license effective phagocytosis remain unclear.
• What they did: Using single-cell RNA sequencing and fate mapping with an MDM-specific Ms4a3 creERT2 -Ai14 mouse line, the study tested Htr2b activation/agonism, MDM-specific Htr2b ablation, and Tfe3 activation for effects on lysosomal biogenesis and phagocytosis.
• The result: Htr2b activation promotes Tfe3 nuclear translocation and lysosomal biogenesis; MDM-specific Htr2b ablation impairs debris clearance and worsens ischemic injury, while agonism or Tfe3 activation restores lysosomal biogenesis and improves post-stroke outcomes.