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.

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.

• Authors: K Wolk, T-C Brembach, D Šimaitė, E Bartnik, S Cucinotta, A Pokrywka, M L Irmer, J Triebus, E Witte-Händel, G Salinas, T Leeuw, H-D Volk, K Ghoreschi, R Sabat
• Journal: The British journal of dermatology (Br J Dermatol) Vol. 185 Issue 1 Pg. 164-176 (07 2021) ISSN: 1365-2133 [Electronic] England
• PMID: 33400270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Chemical References

• Membrane Proteins
• Tumor Necrosis Factor-alpha
• Granulocyte Colony-Stimulating Factor
• ADAM Proteins
• ADAM8 protein, human

Topics

• ADAM Proteins
• Granulocyte Colony-Stimulating Factor
• Hidradenitis Suppurativa
• Humans
• Keratinocytes
• Membrane Proteins
• Neutrophils
• Skin
• Tumor Necrosis Factor-alpha