Peripheral immune response and axonal degeneration in the hind paw skin of mice with experimental autoimmune encephalomyelitis

• EAE leads to significant changes in the innervation density of hind paw skin. • Responses are sex specific and difference in reinnervation emerged by four weeks post-immunization. • Increased inflammation is also observed in the hind paw skin at disease onset that coincided with tactile hypersensitivity. Multiple sclerosis (MS) is traditionally considered a central nervous system (CNS) disease characterized by chronic inflammation and demyelination in the brain and spinal cord, often resulting in debilitating neuropathic pain. While the primary mechanisms of pain in MS are attributed to central mechanisms, recent evidence suggests that peripheral nervous system (PNS) changes may also contribute. Peripheral neurons in the dorsal root ganglia (DRG), which relay sensory information to the CNS, can undergo inflammation-induced structural and functional changes that amplify pain sensitivity. In human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), inflammation and neuronal injury have been observed in the DRG, yet the role of the PNS in MS pain remains underexplored. To investigate peripheral contributions to pain in EAE, we examined disease-induced changes in hind paw cutaneous tissue and found increased inflammation at disease onset that coincided with tactile hypersensitivity. Intraepidermal nerve fiber (IENF) loss was observed in both sexes at disease onset; however, a sex-specific difference in reinnervation emerged by four weeks post-immunization, with females exhibiting significant reinnervation while males did not. These findings identify sex-dependent patterns of peripheral innervation during EAE and raise the possibility that peripheral mechanisms may contribute differently across sexes.