Location: Diet, Genomics and Immunology LaboratoryTitle: The regulatory actions of retinoic acid on M2 polarization of porcine macrophages
|PERRY, TRINITY - Medimmune Vaccines, Inc|
Submitted to: Developmental and Comparative Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/30/2019
Publication Date: 4/8/2019
Citation: Chen, C.T., Perry, T.L., Chitko-Mckown, C.G., Smith, A.D., Cheung, L., Beshah, E., Urban Jr, J.F., Dawson, H.D. 2019. The regulatory actions of retinoic acid on M2 polarization of porcine macrophages. Developmental and Comparative Immunology. 98(9):20-23. https://doi.org/10.1016/j.dci.2019.03.020.
Interpretive Summary: The macrophage represents a population of cells that regulate innate immunity in mammals. These cells differentiate into sub-populations that express unique patterns of genes that orchestrate appropriate protective responses to intra cellular (called M1) or extra cellular pathogens (called M2 or alternative activation), respectively. M1 macrophages are pro inflammatory and M2 macrophages tend to be anti-inflammatory. This skewing of the macrophages toward an M2 phenotype occurs in response to the cytokine, IL-4. Previously we showed that, a partial alternatively-activated state also occurs after the administration of the most active vitamin A metabolite, retinoic acid (RA), to macrophages in culture. This included increasing the messenger RNA of several cytokines, either alone or in response to IL-4, that recruit other cell types to the site of a extra cellular parasite infection. In the current study, we further characterize the effects of RA on alternatively activated macrophage development. We identified 23 genes that are independently induced by RA and IL-4. We also identified several more genes that increase or decrease synergistically, when IL-4 and RA are given to the cells. These genes are associated with the M2 activation state in other species. We also observed an independent reduction in phagocytosis of the extra cellular pathogen, Staphylococcus aureus, in cells treated with IL-4 or RA. Last, we observed that RA and IL-4 up-regulated the anti-inflammatory protein, IL-1R antagonist (ILRN). Given the prevalence of allergic and inflammatory diseases worldwide and the close similarities in the porcine and human immune responses, these findings have important implications for the nutritional regulation of inflammation at mucosal surfaces.
Technical Abstract: We previously demonstrated that the most bioactive vitamin A metabolite, all-trans retinoic acid (ATRA), increased T helper 2-associated responses induced in pigs by infection with the parasitic nematode Ascaris suum. We also showed 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, several mechanisms whereby ATRA affects IL-4 signaling are profiled using large-scale real time PCR and RNASeq. analysis. Twenty three genes associated with M2a markers in other species were independently upregulated by both IL-4 and ATRA, including the adenosine receptor A2B (ADORA2B), cysteinyl leukotriene receptor 2 (CYSLTR2) and the vitamin D receptor (VDR). ATRA enhanced IL-4 up-regulation of Hepatitis A virus cellular receptor 2 (HAVCR2) and transglutaminase 2 (TGM2) and further repressed IL-4 down-regulated CD163 and Cytochrome b-245, beta polypeptide (CYBB) mRNA. Macrophages treated with ATRA exhibited a dose-dependent reduction in phagocytosis of opsonized Staphylococcus aureus. In addition, the combination of IL-4 and ATRA up-regulated the anti-inflammatory protein, IL-1R antagonist (ILRN). These data indicate that ATRA induces a state of partial alternative activation in porcine macrophages, and amplifies certain aspects of M2a activation induced by 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.