Spinal cord injury (SCI) often caused permanent functional impairment, significantly burdening families and society (Yuan et al., 2015). Effective strategies for promoting neurological recovery after SCI were increasingly important. SCI consisted of two stages: primary and secondary. Secondary injury, unlike primary injury, was reversible and involves pathological events such as edema, glial scar formation, ischemia, electrolyte imbalance, excitotoxicity, cell apoptosis, and inflammation (Anjum et al., 2020; Hu et al., 2023a). The proliferative effect of SCI-induced reactive astrocytes around the injury site changed over time (Clifford et al., 2023; Hellenbrand et al., 2021). Astrocytes initially released neurotrophic factors and limited inflammation, aiding axonal regeneration after SCI (Hellenbrand et al., 2021). Reactive astrocytes enlarged, proliferated, and migrated to the injury site, forming glial scars that hindered the repair and regeneration of damaged neural tissue (Pang et al., 2022). After injury, activated microglia proliferate and migrate to engulf damaged cellular fragments, preserving physiological balance. Activated microglia polarize into M1 or M2 phenotypes. M1 phenotype polarization is linked to inflammation and neurodegeneration, while M2 polarization is associated with debris phagocytosis and tissue repair (Hellenbrand et al., 2021; Xu et al., 2023; Li et al., 2023). Following spinal cord injury, many microglia are activated, altering their morphology and function, especially those linked to the M1 phenotype. M1 microglia secrete inflammatory cytokines, leading to neuronal cell death (Brockie et al., 2021). Studies show that microglial activation is a major cause of secondary injury after spinal cord injury, and inhibiting it can reduce tissue damage (Fu et al., 2023; Liu et al., 2023; Wei et al., 2023; Xue et al., 2022; Ma et al., 2023).

Astrocytes were vital for retinal ganglion cell health. Research showed that lacking SPP1 (secreted phosphoprotein 1) in aging and glaucoma mouse models can hasten ganglion cell aging, raise intraocular pressure, and damage the optic nerve (Li and Jakobs, 2022). SPP1-ITGAV indicated robust communication between microglia and neurons in the meninges (Zhang et al., 2023). During early myelin regeneration, HA-labeled cells exhibited a reduced inflammatory response, marked by halted CXCL10 production and increased SPP1 and Timp1 expression, which were linked to regeneration and axonal repair (Schröder et al., 2023). Spp1 regulated neurodegeneration and regeneration after sciatic nerve injury in rats via the c-Fos, PKC α, and p-ERK/ERK pathways. These results provided new insights into Spp1's role in Wallerian degeneration (WD) (Liu et al., 2017). In 2021, a study identified Anxa1, Snap25, and Spp1 as key factors in spinal cord injury repair and regeneration (Fang et al., 2021).

The MK2 signaling pathway was involved in cervical spinal inflammation from chronic compression, and its inhibition may improve outcomes and prevent neurological dysfunction (Song et al., 2015). MK2 expression in the peripheral blood of spinal cord injury patients was higher than in healthy controls. Several studies have shown that targeting MK2 signaling can promote the inflammatory response caused by spinal cord injury and facilitate spinal cord repair (Page et al., 2023; Gao et al., 2018; Zhang et al., 2018; Zhao et al., 2021; Yu et al., 2021; Wang et al., 2018a). The inhibition of MK2 signal interferes with M1 polarization of microglia (Zhao et al., 2021; Yu et al., 2021) and suppresses NLRP3 inflammasome (Na et al., 2020), thereby alleviating neuroinflammatory response. PF-3644022, which inhibited the MK2 signaling pathway, reduced inflammatory factors TNF-α, NF-κB, and IL-1β, while increasing M2 microglia and decreasing M1 microglia in mice with spinal cord injury (Yu et al., 2021). Based on the significant role of the MK2 signaling pathway in the inflammatory response following spinal cord injury, we hypothesized that MK2 functioned as a downstream mediator of SPP1, contributing to SPP1's regulation of spinal cord injury repair, the neuroinflammatory response, and microglial activation. In this study, we developed an animal model of spinal cord injury to investigate the spatiotemporal expression of SPP1 and its effects on spinal cord damage repair. In addition, we also assessed the activation status of microglia and the polarization of M1 and M2 phenotypes. To verify the role of MK2 signaling, we administered PF-3644022 to determine whether MK2 signaling was a crucial downstream molecule regulated by SPP1 in the spinal cord injury repair and the inflammatory response.