IL-25 and B cells in atherosclerosis

Abstract: Atherosclerosis is a chronic inflammatory disease of medium and large vessels of the body which is mainly characterized by the formation of lipid rich plaques within the arterial tissue. It is the most common cause of cardiovascular disease leading to clinical manifestations of coronary artery and cerebrovascular disease. Immune responses targeting modified low density lipoprotein (LDL) play an important role in atherosclerosis. Moreover, Th1 immune responses have inextricably been associated with disease progression while the role of Th17 and Th2 related immune responses is less clear.
In the present work we report that different B cell subsets could potentially be used as biomarkers for the prediction of future stroke events. Specifically, our findings demonstrate an association between high levels of CD19+CD40+ cells and a decreased risk of stroke while high levels of CD19+CD86+ B cells were associated with an increased risk.
Another main focus was the investigation of the role of IL-25 in atherosclerosis. In order to tackle this, the cytokine was both administered and blocked in hypercholesterolaemic apoE-/- mice. Interestingly, an atheroprotective effect of the cytokine was observed. Regarding exogenous IL-25 administration, the proposed mechanism of atheroprotection implicates the increase of IgM antibodies targeting phosphorylcholine (PC), a major epitope on oxidized LDL (oxLDL) via innate lymphoid cell type 2 (ILC2)-derived IL-5. We suggest that the essential trigger for this mechanism is the expansion of ILC2s.
Additionally, blockade of endogenous IL-25 at the onset of atherosclerosis led to increased plaque formation of unstable phenotype, accompanied by a Th1/Th17 shift of the cytokine balance in the spleen of the mice. The above mentioned findings suggest that signaling through IL-25 during early plaque formation possibly regulates protective immune mechanisms and that disruption of that signaling leads to the dominance of pro-inflammatory immune responses.
Due to the atheroprotective effect of IL-25 in mice we also investigated its effect on human peripheral blood mononuclear cells (hPBMCs). IL-25 was shown to dampen Th17 and Th1-related immune responses in hPBMCs while in the presence of oxLDL it dampens Th1 and promotes Th2-related immune responses. The above mentioned findings indicate that IL-25 could potentially have a protective role in human atherosclerosis.