Background Key pathogenic events of psoriasis and atopic eczema (AE) are misguided immune reactions of the skin. IL‐17C is an epithelial‐derived cytokine, whose impact on skin inflammation is unclear. Objective We sought to characterize the role of IL‐17C in human ISD. Methods IL‐17C gene and protein expression was assessed by immunohistochemistry and transcriptome analysis. Primary human keratinocytes were stimulated and expression of cytokines chemokines was determined by qRT‐PCR and luminex assay. Neutrophil migration towards supernatant of stimulated keratinocytes was assessed. IL‐17C was depleted using a new IL‐17C‐specific antibody (MOR106) in murine models of psoriasis (IL‐23 injection model) and AE (MC903 model) as well as in human skin biopsies of psoriasis and AE. Effects on cell influx (mouse models) and gene expression (human explant cultures) were determined. Results Expression of IL‐17C mRNA and protein was elevated in various ISD. We demonstrate that IL‐17C potentiates the expression of innate cytokines, antimicrobial peptides (IL‐36G, S100A7 and HBD2) and chemokines (CXCL8, CXCL10, CCL5 and VEGF) and the autocrine induction of IL‐17C in keratinocytes. Cell‐free supernatant of keratinocytes stimulated with IL‐17C was strongly chemotactic for neutrophils, thus demonstrating a critical role for IL‐17C in immune cell recruitment. IL‐17C depletion significantly reduced cell numbers of T cells, neutrophils and eosinophils in murine models of psoriasis and AE and led to a significant downregulation of inflammatory mediators in human skin biopsies of psoriasis and AE ex vivo. Conclusion IL‐17C amplifies epithelial inflammation in Th2 and Th17 dominated skin inflammation and represents a promising target for the treatment of ISD.

Bone-marrow-derived mast cells are matured from bone marrow cells in medium containing 20% fetal calf serum (FCS), interleukin (IL)-3 and stem-cell factor (SCF) and are used as in vitro models to study mast cells (MC) and their role in health and disease. In vivo, however, BM-derived hematopoietic stem cells account for only a fraction of MC; the majority of MC in vivo are and remain tissue resident. In this study we established a side-by-side culture with BMMC, fetal skin MC (FSMC) or fetal liver MC (FLMC) for comparative studies to identify the best surrogates for mature connective tissue MC (CTMC). All three MC types showed comparable morphology by histology and MC phenotype by flow cytometry. Heterogeneity was detected in the transcriptome with the most differentially expressed genes in FSMC compared to BMMC being Hdc and Tpsb2. Expression of ST2 was highly expressed in BMMC and FSMC and reduced in FLMC, diminishing their secretion of type 2 cytokines. Higher granule content, stronger response to FcεRI activation and significantly higher release of histamine from FSMC compared to FLMC and BMMC indicated differences in MC development in vitro dependent on the tissue of origin. Thus, tissues of origin imprint MC precursor cells to acquire distinct phenotypes and signatures despite identical culture conditions. Fetal-derived MC resemble mature CTMC, with FSMC being the most developed.

ZusammenfassungAcne inversa/Hidradenitis suppurativa (AI/HS) ist eine chronisch-entzündliche Hauterkrankung, die durch das rezidivierende Auftreten von entzündlichen Knoten, Abszessen, Fistelgängen und Narben v. a. in der Axillär-, Inguinal- und Perianalregion charakterisiert ist. In den letzten Jahren rückte die Erforschung der pathophysiologischen Grundlagen der AI/HS zunehmend in den wissenschaftlichen Fokus. Parallel dazu wurde die Wirksamkeit neuer anti-inflammatorischer Therapien in klinischen Studien untersucht, die zum Teil schon Eingang in die klinische Routine gefunden haben. Schwerpunkt dieses Review ist es, den aktuellen Stand der AI/HS zugrundliegenden pathophysiologischen Mechanismen darzustellen und die sich daraus ergebenden Konsequenzen sowohl für die konservative als auch für die operative Therapie abzuleiten.