CD9 AS A DRIVER OF NEUROPHATIC PAIN THROUGH ADAPTIVE IMMUNITY AFTER SPINAL CORD INJURY

Spinal cord injury (SCI) triggers a complex immune response that critically influences motor recovery. Beyond the primary injury and motor impairment, SCI is accompanied by numerous secondary conditions, including persistent inflammation and chronic neuropathic pain. Our laboratory has identified, for the first time, CD9 as a novel vascular injury-induced player following SCI. CD9 is a tetraspanin protein known to regulate cell adhesion and growth, and to modulate immune responses by promoting the transendothelial migration of leukocytes into tissues. Following SCI, CD9 expression is significantly upregulated in mouse endothelial cells during the acute phase of injury (3–7 days post-injury, dpi), with a pronounced expression on the caudal side of the lesion. As injury progresses, CD9 overexpression is also sustained in immune cells, peaking at 7 dpi, a critical time window associated with lymphocyte infiltration and the transition from innate to adaptive immunity. In CD9 knockout (KO) mice, locomotor recovery is impaired compared with wild-type (WT) mice; however, CD9 KO mice display protection against cold thermal hypersensitivity (allodynia) at 7 dpi. This phenotype correlates with alterations in the intraspinal cytokine profile: CD9 KO mice exhibit reduced levels of IL-6, IL-5, and CD40, molecules involved in B cell activation, alongside increased levels of IL-2, TNF-α, and VCAM, further supporting a shift toward adaptive immune responses. Given the established role of adaptive immunity, particularly B cells, in the development of neuropathic pain, we hypothesize that CD9 plays a critical role in B cell activation, thereby modulating allodynia and neuropathic pain following SCI.