The British journal of dermatology · 2021
Activity and components of the granulocyte colony-stimulating factor pathway in hidradenitis suppurativa.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
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.