# Targeted deletion of EMMPRIN in microglia/macrophages mitigates neuronal death in intracerebral hemorrhage

## TL;DR

Deleting EMMPRIN in brain immune cells reduces neuron death and improves recovery after brain hemorrhage.

## Contribution

Targeted deletion of EMMPRIN in microglia/macrophages is shown to mitigate ICH-induced neuronal death and promote brain repair.

## Key findings

- EMMPRIN deletion in microglia/macrophages reduced neuronal death and improved neurological outcomes after ICH.
- EMMPRIN promotes neurotoxicity via MMPs, p38 MAPK, MEF2C, and Bcl2 pathways.
- EMMPRIN deletion enhanced neurogenesis and oligodendrogenesis in the brain after ICH.

## Abstract

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high mortality and limited therapeutic options. Microglia and macrophages are rapidly recruited to the lesion site and contribute substantially to secondary brain injury. However, the key molecular mediators that drive their neurotoxic effects remain incompletely understood.

We investigated the role of extracellular matrix metalloproteinase inducer (EMMPRIN, also known as CD147) in promoting microglia/macrophage-mediated neurotoxicity after ICH. EMMPRIN was selectively deleted in myeloid cells using both AAV-mediated knockdown and CX3CR1Cre:EMMPRINfl/fl mice. Neuronal survival and functional outcomes were assessed using histological, molecular, and behavioral analyses.

Targeted deletion of EMMPRIN in microglia/macrophages significantly reduced neuronal death and improved neurological recovery following ICH. Mechanistically, EMMPRIN-mediated neurotoxicity was associated with elevated expression of matrix metalloproteinases and enhanced activation of the p38 mitogen-activated protein kinase (MAPK) pathway, and with downstream engagement of myocyte enhancer factor 2 C (MEF2C) and B-cell lymphoma 2 (Bcl2). Notably, EMMPRIN deletion also enhanced neurogenesis and oligodendrogenesis in the perihematomal region, suggesting a potential role in promoting endogenous brain repair.

These findings establish EMMPRIN elevation in myeloid cells as a prominent regulator of ICH pathophysiology and a promising therapeutic target to limit secondary injury and promote brain repair.

The online version contains supplementary material available at 10.1186/s13024-025-00917-x.