GPNMB attenuates neuroinflammation and improves ischemic stroke via modulation of PI3K/Akt and p38 MAPK signaling pathways.

Abstract

Background: Ischemic stroke is a leading cause of disability and mortality worldwide, with limited effective treatments. Neuroinflammation plays a crucial role in the progression of ischemic brain injury. Glycoprotein nonmetastatic melanoma protein B (GPNMB) has emerged as a potential regulator of inflammation, but its role and underlying mechanisms in ischemic stroke remain largely unknown.

Methods: We investigated the expression profile, functional significance, and molecular pathways of GPNMB in ischemic stroke using a mouse model of middle cerebral artery occlusion (MCAO), transcriptome sequencing, and human serum samples. The effects of GPNMB knockdown on stroke outcomes, neuroinflammation, and neuronal damage were assessed in vivo. Bioinformatic analyses and experimental validation were performed to identify the downstream signaling pathways of GPNMB.

Results: GPNMB was highly upregulated in the ischemic brain, with its expression peaking at 3-7 days post-MCAO. Serum GPNMB levels were elevated in ischemic stroke patients and correlated with stroke severity. GPNMB knockdown exacerbated stroke outcomes, neuroinflammation, and neuronal damage. Mechanistically, GPNMB positively modulated the PI3K/Akt/GSK3β pathway while negatively regulating p38 MAPK, JNK, and ERK activation. GPNMB knockdown enhanced the expression of NF-κB, a master transcriptional regulator of inflammation.

Conclusion: GPNMB is highly upregulated in the ischemic brain and confers neuroprotection against ischemic injury by modulating neuroinflammation via the PI3K/Akt and p38 MAPK signaling pathways.