IL-17-MICROBIOTA CROSSTALK REGULATES PERIPHERAL NERVE REGENERATION

Peripheral nervous system (PNS) injuries often result in chronic pain, impaired motor function, and considerable economic burden. Immune cells play pivotal roles in PNS repair by clearing debris, modulating inflammation, and promoting regeneration through the release of growth factors. Whereas the contributions of macrophages and neutrophils are well documented, the involvement of T cells, particularly IL-17-producing T cells, remains poorly understood. IL-17A (referred to as IL-17) triggers inflammatory responses, while also promoting tissue repair. Importantly, there is a bidirectional relationship between IL-17 and the gut microbiota: microbial cues influence IL-17 production, and IL-17, in turn, shapes the microbiota. Here we hypothesized that IL-17 regulates nerve regeneration in a microbiota-dependent manner. Using flow cytometry, we identified gamma-delta T cells as the main source of IL-17 in the crushed mouse sciatic nerve. IL-17-producing gamma-delta T cells accumulated early in the injured nerve, peaking at 3 days post-injury, and this recruitment was abolished with a broad-spectrum antibiotic treatment, implicating microbiota-derived cues. Functional studies showed that IL-17-deficient (Il17-/-) mice exhibited incomplete motor recovery, elevated electrophysiological activity, dysregulated expression of regeneration markers and impaired axonal myelination, when compared with their Il17+/+ littermate controls and when housed separately according to their genotype. Remarkably, these deficits were prevented when Il17-/- mice were co-housed with Il17+/+ littermates, indicating that microbiota sharing restores the regenerative capacity. Collectively, our findings reveal a key crosstalk between IL-17 and the gut microbiota that promotes sciatic nerve regeneration, pinpointing novel mechanistic insights to be explored as potential therapeutic targets for PNS degenerative diseases.