Activity and components of the G-CSF pathway in hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by painful, purulent, and destructive skin alterations in intertriginous areas. 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. 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. 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. 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. 

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