Taghavie-Moghadam, Parésa L.Gjurich, Breanne N.Jabeen, RukhsanaKrishnamurthy, PurnaKaplan, Mark H.Dobrian, Anca D.Nadler, Jerry L.Galkina, Elena V.2017-07-252017-07-252015-11Taghavie-Moghadam, P., Gjurich, B., Jabeen, R., Krishnamurthy, P., Kaplan, M. H., Dobrian, A. D., … Galkina, E. V. (2015). STAT4 Deficiency Reduces the Development of Atherosclerosis in mice. Atherosclerosis, 243(1), 169–178. http://doi.org/10.1016/j.atherosclerosis.2015.08.0451879-1484https://hdl.handle.net/1805/13583Atherosclerosis 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.en-USPublisher PolicyAtherosclerosisgeneticsInterferon-gammametabolismMacrophagescytologyPlaque, AtheroscleroticSTAT4 Transcription FactorTh1 CellsArticle