Transcriptional-secretory uncoupling in RDEB skin creates a non-permissive microenvironment for sensory nerve...

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by mutations in COL7A1 gene, leading to chronic injury, inflammation, and debilitating sensory symptoms, including pain and itch. While structural defects in the dermo-epidermal junction are well characterized, the mechanisms underlying impaired sensory reinnervation and neuropathic manifestations remain poorly understood. Here, we investigated whether defective reinnervation in RDEB is driven by intrinsic neuronal deficits or by alterations in the cutaneous microenvironment. Using a prospective cohort of RDEB patients with small fiber neuropathy (SFN), combined with high-resolution digital PCR and multiplex cytokine profiling, we analyzed the transcriptional and secretory responses of wounded skin and primary keratinocytes. RDEB tissue exhibited a markedly blunted transcriptional response to injury, with failure to induce key inflammatory, proteolytic, and axonal guidance genes, despite a sustained pro-inflammatory secretome characterized by elevated IL-6, TNF-α, IL-1β, CCL2, and MMP9. Functionally, RDEB blister fluid induced growth cone collapse and impaired neurite outgrowth in sensory neurons. These findings reveal a dissociation between transcriptional activation and extracellular signalling, resulting in a non-permissive niche for nerve regeneration. We propose that this altered microenvironment simultaneously impairs reinnervation and promotes maladaptive nociceptive signalling, providing a mechanistic link between chronic denervation and neuropathic pain in RDEB.