All-trans retinoic acid suppresses IL-4 and IL-13 production in Th2 cells by modulating the nuclear receptor RARα,...

All-trans retinoic acid (atRA), the bioactive component of vitamin A, plays a pivotal role in various biological processes. atRA, essential for embryonic development and immune functions, primarily mediates its regulatory effects by interacting with the nuclear receptor RARα (retinoic acid receptor α). atRA-bound RARα enters the nucleus and forms a heterodimer with RXR (retinoid X receptor). This heterodimer can then interact with various transcription factors to form regulatory complexes that influence gene expression. While the role of atRA in regulating the type 2 immune response has been studied, further exploration into its specific involvement in Th2 cell differentiation is necessary to fully elucidate underlying mechanisms and assess its therapeutic potential. Our study shows that atRA suppressed the Th2 phenotype by downregulating type 2 transcription factors such as Spi1 and cMaf, without altering Gata3 expression. atRA also reduced IL-4 and IL-13 production, while enhancing IL-5 expression, potentially through upregulation of Gfi1. atRA increased the Gfi1 recruitment to the Il4 and Il13 promoters, along with the common enhancer Ecr (evolutionarily conserved region). RARα, which is typically an inducer of Il4 and Il13, was observed to decrease recruitment to these loci in atRA-treated Th2 cells. Comparative gene expression analysis revealed a reduction in inflammatory responses in atRA-treated Th2 cells. Furthermore, these cells exhibited a negative correlation with epigenetic modifications and nuclear receptor activity among other biological processes. Collectively, our findings suggest that atRA can effectively suppress the Th2 phenotype in vitro, through the regulation of key type 2 transcription factors and pathways, indicating its potential therapeutic implications for limiting type 2 immune responses.