Retinoic acid potentiates inflammatory cytokines in human mast cells: Identification of mast cells as prominent constituents of the skin retinoid network

• Mature mast cells from human skin are susceptible to retinoic acid.
• Retinoids increase inflammatory cytokines via RARA without affecting degranulation.
• MCs are enriched in retinoid network components if weighed against other skin cells.

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.

Graphical AbstractFigure optionsDownload high-quality image (121 K)Download as PowerPoint slide