Retinoic acid potentiates inflammatory cytokines in human mast cells: identification of mast cells as prominent constituents of the skin retinoid network.
Retinoic acid (RA), the active vitamin-A-metabolite, has well-established functions in skin homeostasis and in the immune system. Skin mast cells (MCs) combine traits of both structures, being of hematopoietic origin, but functional in the skin environment. It remains largely unknown whether mature MCs are targeted by the retinoid network. Here, we demonstrate that human skin MCs display substantial susceptibility to RA by which they are instructed to increase pro-inflammatory mediators (IL-1β, IL-8, TNF-α) but not histamine release. The effects are observed at physiological RA levels, in different microenvironments, and are largely donor-independent. RA susceptibility is owed to the cells' abundant expression of RARA, the receptor mediating MC cytokine responses. Unexpectedly, bioinformatics calculations on the FANTOM5 expression atlas revealed general enrichment of retinoid network components in MCs against other skin cells, and MCs rapidly upregulated RA responsive genes. In conclusion, MCs are important yet hitherto overlooked retinoid targets in the skin.
Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany. Electronic address: magda.babina@charite.de.
Magda
M
Babina
Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany.
Sven
S
Guhl
Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa, Japan; RIKEN Omics Science Center, Yokohama, Kanagawa, Japan.
Efthymios
E
Motakis
Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany.
Metin
M
Artuc
Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany.
Tarek
T
Hazzan
Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany.
Margitta
M
Worm
Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa, Japan; RIKEN Omics Science Center, Yokohama, Kanagawa, Japan.
Alistair R R
AR
Forrest
Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany.
Torsten
T
Zuberbier
D002460:Cell Line; D060833:Cellular Microenvironment / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051917:Leukosialin / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D016207:Cytokines; D018836:Inflammation Mediators; D051917:Leukosialin; D018168:Receptors, Retinoic Acid; D014212:Tretinoin
Cytokines; Mast cells; Retinoic acid; Retinoic acid receptor; Retinoids; Skin