Submitted to: Infection and Immunity
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/6/2009
Publication Date: 3/30/2009
Citation: Dawson, H.D., Solano Aguilar, G., Beal, M.E., Beshah, E., Vangimalla, V.R., Jones, E., Botero, S., Urban Jr, J.F. 2009. Localized Th1-, Th2-,and inflamation-associated hepatic and pulmonary immune responses in Ascaris-infected swine are increased by retinoic acid. Infection and Immunity. 77(6):2576-87. Interpretive Summary: The CD4+ T cell represents a population of lymphocytes that regulate acquired immunity in mammals. These cells differentiate into sub-populations (Th1 cells and Th2 cells) and express a particular pattern of cytokines that orchestrate appropriate protective responses to intracellular and extracellular pathogens, respectively. A skewing of the immune response toward a Th1 phenotype has been consistently observed in vitamin A (VA) deficient mice. Conversely, a skewing of the immune response toward a Th2 phenotype accompanies VA or retinoic acid (RA) administration to mice; however, data describing potential mechanisms for these phenomena are often contradictory. Furthermore, species differences limit extrapolation of data on experimental interaction between nutrition and immunology from mice to humans. In the current study, we demonstrate that retinoic acid, an active form of vitamin A, increased localized Th1- and Th2-associated hepatic and pulmonary immune responses in Ascaris-infected swine. We observed a dramatic increase in the number of eosinophils accumulating in the lung and increased expression of two eosinophil-attracting cytokines, CCL11 and CCL26, due to infection. These were all increased by retinoic acid. A functional CCL26 homologue has not been identified in rodents. Given the prominent role that eosinophil migration into pulmonary tissue plays in asthma, allergy, and nematode parasite infection, the pig can serve as a useful model for the study of allergic diseases mediated by CCL26 in humans. Taken together, these data could help explain the often confounding and contradictory responses observed in inbred rodent strains supplemented with VA and other retinoids compared to humans, and help nutritionists determine more appropriate strategies for use of VA to affect immune function.
Technical Abstract: Pigs infected with Ascaris suum were treated with all-trans retinoic acid (ATRA) on d–1, d+1, d+3 of infection. Control or infected pigs were given 100 (LD-ATRA) or 1,000 (HD-ATRA) µg/kg ATRA in corn oil, or corn oil alone, and sacrificed at 7 and 14 days after inoculation (DAI) with infective eggs. At 7 DAI, plasma aspartate animotransferase levels were elevated in infected animals given LD-ATRA. Plasma IL-4 levels were significantly elevated in the infected pigs fed LD- and HD-ATRA at 7 DAI relative to control animals. There was also a significant increase in plasma IL-12p70 in infected pigs given LD-ATRA. At 7 and 14 DAI, LD-ATRA and HD-ATRA significantly augmented infection- induced lung eosinphilia. Large scale real time RT-PCR analysis was used to assess localized expression of genes likely to be associated with these observations. Infected pigs had higher hepatic levels of mRNA for T helper 2 (Th2)-associated cytokines, mast cell markers, and T regulatory (Treg) cells at 7 DAI compared to uninfected pigs. Infected pigs that received LD-ATRA had higher hepatic levels of IL4, IL13, CCL11, CCL26, CCL17, CCL22, and TPSB1 compared to uninfected pigs. In addition, they had higher expression of Th1-associated markers (IFNG, IL12B, and TBX21), the CXCR3 ligand (CXCL9), IL1B, and the putative Treg marker, TNFRSF18. In lung, LD-ATRA increased the expression of IL4, IL13, IL1B, IL6, CCL11, and CCL26 in infected animals. Expression of CCL26 was up-regulated by IL-4 and IL-13 in a swine epithelial cell line and the expression of CCL11, CCL17, and CCL26 were up-regulated by IL4 and IL13 in alveolar macrophages. These data indicate that ATRA augments both a Th1-, Th2-, and inflammation-associated response in the liver and lungs of swine infected with A. suum.