Abstract 130: Il-10 Regulates the Immunoregulatory Response in the Regression of Atherosclerosis

We have previously shown that dietary administration of conjugated linoleic acid (CLA) induces regression of pre-established atherosclerosis in the apoE -/- mouse, via modification of inflammatory cell function. However, the exact mechanism through which this occurs has not been elucidated. Here we describe a functional role for signaling of the anti-inflammatory cytokine, IL-10, in atherosclerosis regression and investigate the consequence of enhanced IL-10 generation on the immune cell population in vivo . Our initial aim was todelineate the atheroprotective mechanisms modulated by CLA. Transcriptomic analysis of aortic tissue in the CLA-induced regression model identified an enrichment of the IL-10 signaling pathway. Further analysis of the network identified increased IL-10 receptor expression (localized to the macrophage cells) and STAT3 phosphorylation; and increased expression of downstream target genes such as the anti-inflammatory cytokine IL-1Ra (by 3.45 ± 0.83 p<0.05 fold) and suppressor of cytokine signaling (SOCS3) (by 2.24± 0.44 p<0.01 fold). Moreover, there was increased circulating IL-10 serum levels in apoE -/- mice fed a CLA supplemented 1% cholesterol diet compared with apoE -/- mice fed a 1% cholesterol diet alone (41.9 ± 8.9 vs 79.8 pg/ml ± 22.4 p<0.01). Interestingly, both IL-10 production and STAT3 phosphorylation was significantly increased in bone marrow derived macrophages from CLA fed mice. We next employed flow cytometry to delineate the phenotype of single cell suspensions of aortae. CLA supplementation regulated immune cell infiltration of the aorta with increased number of the anti-inflammatory Ly6C lo monocytes evident during regression (29±8 vs 77±14cells/mg aorta p<0.05). In addition, CLA-induced regression was associated with increased polarization towards an anti-inflammatory M2 phenotype, confirmed by an enrichment of M2 genes in the aorta, which occurred as a consequence of increased aortic IL-10 production. In summary CLA mediated induction of IL-10 signaling alters the immunoinflammatory response to atherosclerosis, with increased volume of Ly6C lo monocytes infiltrating the regressing lesions and directed polarization of macrophages towards an M2 phenotype in the plaque microenvironment.