Details

Autor(en) / Beteiligte

• Wolk, K.
• Brembach, T.‐C.
• Šimaitė, D.
• Bartnik, E.
• Cucinotta, S.
• Pokrywka, A.
• Irmer, M.L.
• Triebus, J.
• Witte‐Händel, E.
• Salinas, G.
• Leeuw, T.
• Volk, H.‐D.
• Ghoreschi, K.
• Sabat, R.

Titel

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

Ist Teil von

• British journal of dermatology (1951), 2021-07, Vol.185 (1), p.164-176

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2021

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Summary Background Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by painful, purulent and destructive skin alterations in intertriginous areas. Objectives We investigated the expression and role in HS of granulocyte colony‐stimulating factor (G‐CSF), the regulator of neutrophil biology, as clinical signs of a neutrophilic granulocyte‐driven inflammation are distinctive in the disease. Methods Skin and blood samples obtained from different cohorts of patients with HS and control individuals were assessed by RNA sequencing, quantitative polymerase chain reaction on reverse transcribed mRNA, and/or enzyme‐linked immunosorbent assay. 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, respectively, induced G‐CSF production by fibroblasts and keratinocytes. These effects were enhanced by tumour necrosis factor (TNF)‐α and IL‐36. Accordingly, fibroblasts separated from HS lesions expressed G‐CSF, and IL‐1 receptor antagonist reduced G‐CSF levels in explanted HS skin. G‐CSF blood levels positively correlated with severity of HS. Elevated lesional G‐CSF receptor levels were linked to upregulation of molecules that contribute to prolonged activation of neutrophils by components of bacteria and damaged host cells [formyl peptide receptor 1 (FPR1), FPR2 and free fatty acid receptor 2 (FFAR2)], neutrophil survival [TNF receptor superfamily member 10C (TNFRSF10C/TRAIL‐R3) and TNF receptor superfamily member 6B], kinases (tyrosine‐protein kinase HCK and hexokinase 3), and skin destruction [MMP25 (matrix metalloproteinase 25) and ADAM8 (disintegrin and metalloproteinase domain‐containing protein 8)]. G‐CSF elevated the expression of FPR1, FFAR2, and TNFRSF10C/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. What is already known about this topic? Hidradenitis suppurativa (HS) is a chronic debilitating skin disorder with a very high, unmet medical need. The diseased skin in patients with HS shows distinct features of a neutrophil‐driven inflammation (e.g. abscess formation, purulent discharge). Granulocyte colony‐stimulating factor (G‐CSF) is the major regulator of neutrophil development, survival and function. What does this study add? HS lesions show highly increased levels of G‐CSF and its receptor. Major G‐CSF inducers are interleukin (IL)‐1β and IL‐17. In neutrophils, G‐CSF upregulates receptors for components of bacteria and damaged host cells, decoy receptors for apoptosis inducers and proteases. The production of skin‐destructive enzymes induced by bacterial components is strengthened by G‐CSF in neutrophils. G‐CSF inducers and molecules upregulated by G‐CSF in neutrophils in vitro are abundant in HS lesions. What is the translational message? G‐CSF is the central element of a pathogenetic pathway in HS. The G‐CSF pathway may contribute to the persistence of abscesses, purulent secretion and progressive skin structure destruction. Targeting G‐CSF or its pathway elements may represent an approach for the treatment of HS and other conditions with neutrophil‐driven inflammation and skin destruction. Linked Comment: E.J. Giamarellos‐Bourboulis. Br J Dermatol 2021; 185:15–16.