Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disease. HS appears to be a primary abnormality in the pilosebaceous-apocrine unit.  We characterized hair follicle stem cells (HF-SC) isolated from HS patients and more precisely the Outer Root Sheath Cells (ORS). We previously showed that ORS isolated from HS patients (HS-ORS) secrete spontaneously IP-10 and RANTES. In this study, we aim to characterize the molecular mechanisms involved in the pro-inflammatory phenotype of HS-ORS. Transcriptomic analysis of HS-ORS highlighted a deregulation of genes involved in cell proliferation and differentiation, and an upregulation of DNA damage response and IFN signature. We observed a perturbation of HF-SC compartment in HS patients with the lack of the quiescent bulge stem cell population and the increase of proliferating progenitor cells. Fork progression analysis revealed a replicative stress which leads to activation of the ATR-CHK1 pathway. Accumulation of ssDNA and micronuclei in the cytoplasm of HS-ORS contributes to STING activation via the DNA sensor IFI16, inducing IFN synthesis and independently of cGAS. Depletion of STING in ORS results in modulation of fork progression. These findings support the notion that, in HS patients, a perturbation of HF-SC homeostasis leading to an increased proliferation induces a replicative stress and an accumulation of cytoplasmic ssDNA, stimulating IFN synthesis through IFI16-STING pathway. This mechanistic analysis of the etiology of HS in the HF-SC compartment establishes, for the first time, a formal link between the genetic predisposition and skin inflammation observed in HS.

Spontaneous replication stress in Hair Follicle Stem Cells leads to inflammation in Hidradenitis Suppurativa