Blockade of semaphorin 3E attenuates neuroinflammation and mechanical hypersensitivity: implications for neuropathic pain therapy.

BACKGROUND AND OBJECTIVES: Macrophage-associated responses at sites of nerve injury are involved in the initiation and persistence of neuropathic pain (NP). Immune semaphorins (SEMAs), including SEMA3A, SEMA3E, SEMA4A, SEMA4D, and SEMA7A, regulate macrophage migration and activation, but their roles in NP remain unclear. This study aimed to identify immune SEMAs associated with NP by analyzing their serum levels and expression in sensory nerve tissues of patients with NP, and to evaluate the potential effects of SEMA-targeted intervention in a mouse model.

METHODS: Serum SEMA levels were measured in 45 patients with NP and 17 age- and sex-matched healthy controls (HCs) using enzyme-linked immunosorbent assay. Using immunohistochemistry, SEMA expression was examined in the peripheral nerves (PNs) and dorsal root ganglia (DRG) from seven autopsied/biopsied patients (four with and three without NP), and in male ICR mice with partial sciatic nerve ligation (PSNL). Additionally, we intraperitoneally injected SEMA-blocking immunoglobulin G (IgG) or control IgG into PSNL-operated mice for 5 consecutive days, either immediately after PSNL (preventive protocol) or from day 14 (therapeutic protocol). Mechanical hypersensitivity was assessed using von Frey filaments. In vitro, mouse DRG neurons treated with or without SEMA3E were analyzed for neurite outgrowth and gene expression.

RESULTS: Serum SEMA3E levels tended to be higher in patients with NP than in HCs, although this difference did not remain significant after correction for multiple comparisons. SEMA3E immunoreactivity appeared to be increased in macrophages in both PNs and the DRG, and was also observed in satellite glial cells in the DRG of patients with NP. Similarly, SEMA3E upregulation was observed in macrophages in the injured PNs of PSNL-operated mice. Administration of SEMA3E-blocking IgG was associated with reduced macrophage-associated signals in PNs and attenuated hypersensitivity in PSNL-operated mice under both treatment protocols. In vitro, SEMA3E was associated with reduced neurite outgrowth in mouse DRG neurons.

CONCLUSION: SEMA3E expression appears to be increased at sites of nerve injury in both patients with NP and a mouse model of NP. Experimental findings from the mouse model suggest that SEMA3E may be associated with pain-related hypersensitivity. SEMA3E blockade might represent a potential therapeutic approach for NP.