Retinoids are a frequently used class of drugs in the treatment of inflammatory as well as malignant skin diseases. Retinoids have differential affinity for the retinoic acid receptor (RAR) and/or the retinoid X receptor (RXR). The endogenous dual RAR and RXR agonist alitretinoin (9-cis retinoic acid) demonstrated remarkable efficacy in the treatment of chronic hand eczema (CHE) patients; however, detailed information on the mechanisms of action remains elusive. Here, we used CHE as a model disease to unravel immunomodulatory pathways following retinoid receptor signaling. Transcriptome analyses of skin specimens from alitretinoin-responder CHE patients identified 231 significantly regulated genes. Bioinformatic analyses indicated keratinocytes as well as antigen presenting cells as cellular targets of alitretinoin. In keratinocytes, alitretinoin interfered with inflammation-associated barrier gene dysregulation as well as antimicrobial peptide induction while markedly inducing hyaluronan synthases without affecting hyaluronidase expression. In monocyte-derived dendritic cells, alitretinoin induced distinct morphological and phenotypic characteristics with low co-stimulatory molecule expression (CD80 and CD86), the increased secretion of IL-10 and the upregulation of the ecto-5′-nucleotidase CD73 mimicking immunomodulatory or tolerogenic dendritic cells. Indeed, alitretinoin-treated dendritic cells demonstrated a significantly reduced capacity to activate T cells in mixed leukocyte reactions. In a direct comparison, alitretinoin-mediated effects were significantly stronger than those observed for the RAR agonist acitretin. Moreover, longitudinal monitoring of alitretinoin-responder CHE patients could confirm in vitro findings. Taken together, we demonstrate that the dual RAR and RXR agonist alitretinoin targets epidermal dysregulation and demonstrates strong immunomodulatory effects on antigen presenting cell functions.

Background: Loss-of-function mutations in the filaggrin (FLG) gene directly alter skin barrier function and critically influence atopic inflammation. While skin barrier dysfunction, Th2-associated inflammation and bacterial dysbiosis are well-known characteristics of atopic dermatitis (AD), the mechanisms interconnecting genotype, transcriptome and microbiome remain largely elusive. Objective: In-depth analysis of FLG genotype-associated skin gene expression alterations and host-microbe interactions in AD. Methods: Multi-omics characterization of a cohort of AD patients carrying heterozygous loss-of-function mutations in the FLG gene (AD(Mut)) (n = 15), along with matched wild-type (AD(Wt)) patients and healthycontrols. Detailed clinical characterization, microarray gene expression and 16 S rRNA-based microbial marker gene data were generated and analyzed. Results: In the context of filaggrin dysfunction, the transcriptome was characterized by dysregulation of barrier function and water homeostasis, while the lesional skin of AD(Wt )demonstrated the specific upregulation of pro-inflammatory cytokines and T-cell proliferation. S. aureus dominated the microbiome in both patient groups, however, shifting microbial communities could be observed when comparing healthy with non-lesional AD(Wt) or AD(Mut) skin, offering the opportunity to identify microbe-associated transcriptomic signatures. Moreover, an AD core signature with 28 genes, including CCL13, CCL18, BTC, SCIN, RAB31 and PCLO was identified. Conclusions: Our integrative approach provides molecular insights for the concept that FLG loss-of-function mutations are a genetic shortcut to atopic inflammation and unravels the complex interplay between genotype, transcriptome and microbiome in the human holobiont. Crown Copyright (c) 2022 Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology. All rights reserved.

Die Haut ist ein häufig von chronischen Erkrankungen betroffenes Organ. Entzündliche, immunvermittelte Dermatosen wie atopische Dermatitis und Psoriasis zeigen neben einer hohen Prävalenz auch einen deutlichen Einfluss auf die Lebensqualität der Betroffenen. Die atopische Dermatitis geht in einem Großteil der Fälle mit einer deutlichen Veränderung mikrobieller Besiedelung der klinisch gesunden als auch betroffenen Haut einher, für die eine klinische Relevanz angenommen wird. Bei der Psoriasis sind zwar Veränderungen mikrobieller Besiedlungen ebenfalls beschrieben, bei dieser Dermatose bleibt eine klinische Relevanz jedoch noch abzuwarten. In den letzten Jahren konnten zunehmende Erkenntnisse in der Mikrobiomforschung gewonnen werden mit daraus resultierender klinischer Relevanz. Der vorliegende Beitrag befasst sich mit dem gestörten Gleichgewicht von Immunsystem und Hautmikrobiom bei chronisch entzündlichen Dermatosen anhand der atopischen Dermatitis und der Psoriasis vulgaris. Es erfolgte eine Literaturrecherche in den Datenbanken von PubMed und Medline (Einträge bis zum 09.04.2021). Bei der atopischen Dermatitis wird der Kolonisierung der läsionalen Haut mit Staphylococcus aureus eine zentrale pathophysiologische Rolle zugeschrieben. Diese wird im Hinblick auf neue Erkenntnisse bezüglich der Biodiversität und immunregulatorischer Prozesse neu beleuchtet. Bei der Psoriasis zeigt sich eine heterogenere Datenlage bezüglich des Mikrobioms und dessen Beitrag zur Krankheitsentstehung. Während bei der atopischen Dermatitis bereits topische Anwendungen zur direkten Beeinflussung des Mikrobioms in Erprobung sind, bedarf es bei der Psoriasis noch weiteren Erkenntnisgewinns bezüglich der pathophysiologischen Bedeutung der Mikrobiota.

Pruritus represents one of the most common symptoms in dermatology and general medicine. Chronic pruritus severely impairs the quality of life of affected patients. During the last two decades a number of modulators and mediator of pruritus have been identified. Recently, Interleukin (IL)-31 and its receptor complex attracted significant interest, as clinical phase two studies demonstrated therapeutic efficacy of the neutralizing IL-31 receptor A (IL-31RA) antibody nemolizumab in patients suffering from atopic dermatitis or prurigo nodularis. IL-31 has also been shown to play relevant roles in allergic contact dermatitis, urticaria, mastocytosis, allergic rhinitis and asthma. Here, we summarize the current knowledge of the novel cytokine IL-31 and its receptor regarding cellular origin, regulation, signaling pathways and their involvement in biological processes such as pruritus, neuronal growth, inflammation, barrier dysfunction and tissue remodeling.

Pruritus represents one of the most common symptoms in dermatology and general medicine. Chronic pruritus severely impairs the quality of life of affected patients. During the last two decades a number of modulators and mediator of pruritus have been identified. Recently, Interleukin (IL)-31 and its receptor complex attracted significant interest, as clinical phase two studies demonstrated therapeutic efficacy of the neutralizing IL-31 receptor A (IL-31RA) antibody nemolizumab in patients suffering from atopic dermatitis or prurigo nodularis. IL-31 has also been shown to play relevant roles in allergic contact dermatitis, urticaria, mastocytosis, allergic rhinitis and asthma. Here, we summarize the current knowledge of the novel cytokine IL-31 and its receptor regarding cellular origin, regulation, signaling pathways and their involvement in biological processes such as pruritus, neuronal growth, inflammation, barrier dysfunction and tissue remodeling.

Background The skin is an organ frequently affected by chronic diseases. Inflammatory, immune-mediated dermatoses such as atopic dermatitis and psoriasis show a high prevalence as well as a significant impact on the quality of life of those affected. In a large proportion of cases, atopic dermatitis is associated with a marked change in microbial colonization of both clinically healthy and affected skin. In psoriasis, changes to this effect have been described, but clinical relevance remains elusive. Aim In recent years, increasing knowledge has been gained in microbiome research with resulting clinical relevance. The present article deals with the disturbed balance of the immune system and the skin microbiome in chronic inflammatory dermatoses on the basis of atopic dermatitis and psoriasis vulgaris. Materials and methods A literature search was performed in PubMed and Medline databases (entries until 09 April 2021). Results Staphylococcus aureus is known to play a central pathophysiological role in atopic dermatitis. This is revisited in light of new insights regarding biodiversity and immunoregulatory processes. In psoriasis, a more heterogeneous body of data emerges regarding the microbiome and its contribution to disease development. Discussion While topical applications to directly influence the microbiome are already being tested in atopic dermatitis, further knowledge regarding the pathophysiological significance of the microbiota is still needed in psoriasis.

Cytokine signaling is transmitted by cell-surface receptors that function as biological switches controlling mainly immune-related processes. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of GFP and mCherry nanobodies fused to transmembrane and intracellular domains of cytokine receptors that phenocopy cytokine signaling induced by nonphysiological homo- and heterodimeric GFP-mCherry ligands. Interleukin 22 (IL-22) signals via both IL-22 receptor α1 (IL-22Rα1) and the common IL-10R2, belongs to the IL-10 cytokine family, and is critically involved in tissue regeneration. Here, IL-22 SyCyRs phenocopied native IL-22 signal transduction, indicated by induction of cytokine-dependent cellular proliferation, signal transduction, and transcriptome analysis. Whereas homodimeric IL-22Rα1 SyCyRs failed to activate signaling, homodimerization of the second IL-22 signaling chain, SyCyR(IL-10R2), which previously was considered not to induce signal transduction, led to induction of signal transduction. Interestingly, the SyCyR(IL-10R2) and SyCyR(IL-22Rα1) constructs could form functional heterodimeric receptor signaling complexes with the synthetic IL-6 receptor chain SyCyR(gp130). In summary, we have demonstrated that IL-22 signaling can be phenocopied by synthetic cytokine receptors, identified a functional IL-10R2 homodimeric receptor complex, and uncovered broad receptor cross-talk of IL-22Rα1 and IL-20R2 with gp130.