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<sup>-/-</sup>Apoe<sup>-/-</sup> vs Apoe<sup>-/-</sup> mice fed chow diet and significantly attenuated atherosclerosis (~31%, p < 0.01) in western diet fed Stat4<sup>-/-</sup>Apoe<sup>-/-</sup> mice. Surprisingly, reduced atherogenesis in Stat4<sup>-/-</sup>Apoe<sup>-/-</sup> 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<sup>-/-</sup>Apoe<sup>-/-</sup>in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe<sup>-/-</sup> M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-A<sup>b</sup>, and CD86 in response to LPS stimulation. Stat4<sup>-/-</sup>Apoe<sup>-/-</sup> MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b<sup>+</sup>F4/80<sup>+</sup>Ly6C<sup>hi</sup> MΦs was reduced in Stat4<sup>-/-</sup>Apoe<sup>-/-</sup> vs Apoe<sup>-/-</sup> 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.
|Original language||English (US)|
|Number of pages||10|
|State||Published - Nov 1 2015|
- Transcription factors
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine