The regulatory actions of retinoic acid on M2a macrophage polarization of porcine and human myeloid-derived cells.

Abstract Previously we demonstrated that the most bioactive vitamin A metabolite, all-trans retinoic acid (ATRA) increased T helper 2-associated responses induced by Ascaris infection of pigs. We also demonstrated, on a limited basis, that ATRA potentiated the mRNA expression of several IL-4 induced chemokines (chemokine (C-C motif) ligand 11 ((CCL11), CCL17, CCL22 and CCL26) associated with alternative activation (M2a) in porcine macrophages in vitro. Herein, we describe several mechanisms whereby ATRA affects IL-4 signaling and extend these findings to porcine monocytes/macrophages and human macrophages. In human THP-1 cells, IL-4 exposure led to an increase in the mRNA for the M2a macrophage-associated chemokines, CCL11, CCL13, CCL17, CCL18, CCL22 and CCL26 as well as the M2a-associated surface markers, CD206, CD209 and CD274. ATRA synergistically increased IL-4–induced CCL2, CCL13, CCL18, CCL22 and CCL26 mRNA and CCL13, CCL18 and CCL26 protein levels while having no effect or slightly down regulating MRC1, CD209 and CD274 mRNA expression. The effects of ATRA on mRNA levels were greater at 24 compared to 48 hrs; however, greater differences in protein levels were observed at 48 hrs for CCL13, CCL18 and CCL26. In contrast to porcine monocytes and macrophages, ATRA decreased IL-4 induced CCL17 mRNA and protein expression in THP-1 cells. Thus, in porcine monocytes and macrophages and in human macrophages, ATRA selectively increased signaling in response to IL-4. Given the prevalence of allergic and parasitic diseases worldwide and the close similarities in the porcine and human immune responses, these findings have important implications for the nutritional regulation of allergic inflammation at mucosal surfaces.