K Wolk1,2, T-C Brembach1,3, D Šimaitė4, E Bartnik5, S Cucinotta1, A Pokrywka6, M L Irmer1, J Triebus1, E Witte-Händel1, G Salinas7, T Leeuw5, H-D Volk8,9, K Ghoreschi6, R Sabat1,10. 1. Psoriasis Research and Treatment Centre, Charité - Universitätsmedizin Berlin, Berlin, Germany. 2. Inflammation and Regeneration of Skin, BIH Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany. 3. University of Potsdam, Institute of Nutritional Science, Department of Food Chemistry, Potsdam, Germany. 4. Data and Data Sciences, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany. 5. Immunology and Inflammation Research, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany. 6. Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin, Berlin, Germany. 7. Transcriptome and Genome Core Unit, University Medical Center Göttingen, Göttingen, Germany. 8. BIH Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany. 9. Institute of Medical Immunology, Charité - Universitätsmedizin, Berlin, Germany. 10. Interdisciplinary group Molecular Immunopathology, Dermatology/Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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.
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: Hideyuki Ujiie; David Rosmarin; Michael P Schön; Sonja Ständer; Katharina Boch; Martin Metz; Marcus Maurer; Diamant Thaci; Enno Schmidt; Connor Cole; Kyle T Amber; Dario Didona; Michael Hertl; Andreas Recke; Hanna Graßhoff; Alexander Hackel; Anja Schumann; Gabriela Riemekasten; Katja Bieber; Gant Sprow; Joshua Dan; Detlef Zillikens; Tanya Sezin; Angela M Christiano; Kerstin Wolk; Robert Sabat; Khalaf Kridin; Victoria P Werth; Ralf J Ludwig Journal: Front Med (Lausanne) Date: 2022-06-09
Authors: Sylke Schneider-Burrus; Athanasia Tsaousi; Sebastian Barbus; Johannes Huss-Marp; Katrin Witte; Kerstin Wolk; Björn Fritz; Robert Sabat Journal: Front Med (Lausanne) Date: 2021-04-27