Work

Effect of microglial Pd1 on glial scar formation after spinal cord injury in mice

Year: 2025

Type: article

Abstract: The cross talk between microglia and astrocytes following spinal cord injury (SCI) greatly decides the prognosis. However, a comprehensive understanding of the molecular mechanisms by which microglia regulate astrocytic activity post-SCI is lacking. Programmed cell death protein 1 (Pdcd1, Pd1) plays a crucial role in modulating immune responses by exerting suppressive effects on microglia and peripheral immune cells within the central nervous system. Previous studies have shown the involvement of Pd1 in the pathogenesis of SCI; however, the role of microglial Pd1 in astrocytic activation and the following glial scar formation remains elusive. Here, we demonstrated that the pharmacological depletion of microglia using minocycline decreased the expression of tumor necrosis factor-alpha and interleukin-6 while concurrently increasing the expression of interleukin-10 following SCI, thereby facilitating motor function recovery in mice. We observed an increase in Pd1 expression in the injured spinal cord after SCI, with precise localization of Pd1 within microglia. Based on Pd1 knockout (KO) mice, we further revealed that Pd1 deficiency disrupted glial scar formation, leading to increased inflammation, impeded nerve regeneration, enlarged tissue damage, and compromised functional recovery following SCI. In vitro study showed that siRNA-mediated inhibition of Pd1 in microglia followed by lipopolysaccharide treatment significantly inhibited astrocyte migration and upregulated the secretion of tumor necrosis factor-alpha and CXCL9 from microglia, indicating that microglial Pd1 regulates glial scar formation through modulating the inflammatory microenvironment. Our study gains a new mechanistic insight into how microglial Pd1 decides the fate of SCI and promotes microglial Pd1 as a promising therapeutic target for SCI.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2025.108489