The Endogenous Dual Retinoid Receptor Agonist Alitretinoin Exhibits Immunoregulatory Functions on Antigen-Presenting Cells

• Published in: International journal of molecular sciences 2023-06, Vol.24 (11), p.9654
• Main Authors: Kislat, Andreas, Olah, Peter, Kuchner, Marcus, Gerber, Peter Arne, Schrader, Jürgen, Meller, Stephan, Homey, Bernhard
• Format: Article
• Language: English
• Subjects: Acids; Agonists; Alitretinoin; Analysis; Antigen-presenting cells; Antigens; Antimicrobial peptides; Biopsy; CD73 antigen; CD80 antigen; CD86 antigen; Chemokines; chronic hand eczema; Dehydrogenases; Dendritic cells; Dendritic structure; Dermatologic agents; Dermatology; Eczema; Exhibitions; Extracellular matrix; Formulae, receipts, prescriptions; Gene expression; Genes; Genotype & phenotype; Health services; Homeostasis; Hyaluronic acid; Immunomodulation; Immunoregulation; Inflammation; Interleukin 10; Keratinocytes; Lymphocytes; Lymphocytes T; Medical research; Medicine, Experimental; Monocytes; Morphology; Nucleotidase; Pharmaceutical industry; Physical characteristics; RAR; Retinoic acid; Retinoic acid receptors; Retinoid X receptors; Retinoids; RXR; Skin; Skin diseases; T cells; Transcriptomes; Vitamin A
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24119654

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- 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.