The role of Interleukin-1 driven inflammation in recessive dystrophic epidermolysis bullosa

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin fragility disease secondary to mutations in COL7A1 and associated with repeated skin erosion, fibrosis and development of lethal cutaneous squamous cell carcinoma. Inflammation has been implicated in all stages of RDEB disease progression, however its mechanism remains unclear. In this study, we quantitated pro- and anti- inflammatory cytokines in the skin of RDEB mouse models and wild type (WT) littermate controls from birth to adulthood. IL-1α was found to be the most elevated pro-inflammatory cytokine at birth. Its level came down briefly at one week of age then significantly upregulated and remained high in later time points. It appears that IL-1α released from damaged epidermal cells triggered the first wave of inflammatory responses during the perinatal period in RDEB, as the peaks of elevation of other pro-inflammatory cytokines, including IL-6, TNF, IFNγ and TGFβ1 in the RDEB skin were behind that of IL-1α. In contrast, the overall levels of IL-1β and IL-1ra, natural inhibitors of IL-1 signaling were not significantly different between the RDEB and WT skin. Importantly, through single cell RNA sequencing (scRNAseq) of skin cells isolated from around 2-week old RDEB and WT mice, we identified a RDEB specific inflammatory fibroblast subset that shares molecular characteristics of IL-1 induced inflammatory cancer associated fibroblast differentiation, for example, expression of PDPN and LIF. Both bioinformatic analysis of scRNAseq and immunohistochemical staining suggest that this inflammatory fibroblast subset is a distinct subpopulation from TGFβ-induced myofibroblasts. We also demonstrated that IL-1α could stimulate PDPN and LIF expression in RDEB mouse and human patient-derived fibroblasts in vitro, further validating the in vivo finding. In summary, our data underscore the role of IL-1α mediated inflammation in RDEB and suggest that treatments that modulate IL-1 signaling may serve as critical therapies for RDEB patients.