Activity and components of the granulocyte colony‐stimulating factor pathway in hidradenitis suppurativa*

Abstract

Background Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by painful, purulent, and destructive skin alterations in intertriginous areas. Objective We investigated the expression and role of granulocyte‐colony‐stimulating factor (G‐CSF), the regulator of the neutrophil biology, in HS since clinical signs of a neutrophilic granulocyte‐driven inflammation are distinctive in the disease. Methods Skin and blood samples obtained from different cohorts of HS patients and control individuals were assessed by RNA‐sequencing, RT‐qPCR, and/or ELISA. Mechanistic studies using keratinocytes, dermal fibroblasts, immune cell populations, and skin biopsies were performed. Results G‐CSF was abundant in HS skin, particularly in inflamed nodules and abscesses. Its levels even exceeded those found in other inflammatory skin diseases. Interleukin (IL)‐1 and IL‐17 induced G‐CSF production by fibroblasts and keratinocytes, respectively. These effects were enhanced by TNF‐α and IL‐36. Accordingly, fibroblasts separated from HS lesions expressed G‐CSF and IL‐1 receptor antagonist reduced the G‐CSF levels in explanted HS skin. G‐CSF blood levels positively correlated with the severity of HS. Elevated lesional G‐CSF receptor levels were linked to the up‐regulation of molecules which contribute to prolonged activation of neutrophils by components of bacteria and damaged host cells (FPR1, FPR2, and FFAR2), neutrophil survival (TRAIL‐R3, TNFRSF6B), kinases (HCK, HK3), and skin destruction (MMP25, ADAM8). G‐CSF elevated the expression of FPR1, FFAR2, and TRAIL‐R3 in neutrophils and synergized with bacterial components to induce skin‐destructive enzymes. Conclusions The G‐CSF pathway engages both tissue and immune cells, is strongly activated in HS lesions, and offers the opportunity to target the neutrophil‐driven inflammation.