STAT4 deficiency reduces the development of atherosclerosis in mice. Issue 1 (November 2015) - Taghavie-Moghadam, Parésa L.
Abstract: Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ∼71% reduction (p < 0.001) in plaque burden in Stat4 −/− Apoe −/− vs Apoe −/− mice fed chow diet and significantly attenuated atherosclerosis (∼31%, p < 0.01) in western diet fed Stat4 −/− Apoe −/− mice. Surprisingly, reduced atherogenesis in Stat4 −/− Apoe −/− mice was not due to attenuated IFNγ production in vivo by Th1 cells, suggesting an at least partially IFNγ-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (MΦs). Stat4 −/− Apoe −/− in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe −/− M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-A b, and CD86 in response to LPS stimulation. Stat4 −/− Apoe −/− MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b + F4/80 + Ly6C hi MΦs was reduced in Stat4 −/− Apoe −/− vs Apoe −/− mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFNγ, and primarily involving the modulation of MΦ responses. Highlights: Stat4 −/− Apoe −/− deficient mice were generated. Stat-4 deficiency resulted in the attenuated atherosclerosis. Reduced atherogenesis was at least partially independent of Th1 cell-derived IFNγ. STAT4 supports pro-inflammatory macrophage response in atherosclerosis.