# AXL Promotes Ischemic Myelin Repair Through Alleviating Myelin Debris Deposition and Lipid Droplets Accumulation

## TL;DR

This study shows that AXL in microglia helps repair myelin after stroke by reducing debris and lipid buildup, offering a potential new therapy target.

## Contribution

The study reveals a novel mechanism by which AXL regulates myelin repair through sphingolipid metabolism and lipid droplet control.

## Key findings

- AXL-deficient microglia show reduced phagocytic capacity and increased lipid droplet accumulation after stroke.
- AXL regulates Smpd1 transcription via EGR1, modulating sphingolipid metabolism and lipid droplet accumulation.
- ASM supplementation in AXL-deficient mice reduces lipid droplets and white matter injury.

## Abstract

Ischemic white matter injury leads to long‐term neurological deficits but currently lacks effective therapies. Although AXL has been implicated in debris clearance and inflammatory regulation, its role in post‐stroke myelin repair remains unclear. Here, we report robust upregulation of microglial AXL in mice after tMCAO. Microglial AXL cKO mice exhibited worse motor and cognitive deficits up to 28 days after tMCAO, accompanied by more severe white matter damage, increased myelin debris, and greater lipid droplets (LDs) accumulation in microglia than WT controls. Longitudinal analysis showed that AXL‐deficient microglia had reduced early phagocytic capacity but increased LDs accumulation and lipid peroxidation at later stages. Transcriptomic profiling revealed altered inflammatory and sphingolipid metabolism pathways in AXL‐deficient microglia. Mechanistically, AXL regulates Smpd1 transcription via EGR1, thereby modulating sphingolipid metabolism and LDs accumulation. Remarkably, supplement with ASM (the Smpd1‐encoded enzyme) in AXL cKO mice reduced LDs accumulation and attenuated ischemic white matter injury. Collectively, these findings identify microglial AXL as an endogenous regulator of myelin repair after ischemic stroke.

Microglial AXL drives white matter repair after stroke by orchestrating the cleanup of myelin debris. Mechanistically, AXL signals through EGR1 to boost Smpd1 transcription, regulating sphingolipid metabolism and preventing lipid droplet toxicity. Restoring the pathway with ASM therapy mitigates damage, positioning AXL as a key node for therapeutic intervention.