STAT4 deficiency reduces the development of atherosclerosis in mice. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Taghavie-Moghadam, Parésa L.; Gjurich, Breanne N.; Jabeen, Rukhsana; Krishnamurthy, Purna; Kaplan, Mark H.; Dobrian, Anca D.; Nadler, Jerry L.; Galkina, Elena V.
• Is Part Of: Atherosclerosis. Volume 243:Issue 1(2015)
• Page Start: 169
• Page End: 178
• Publication Date: 2015-11
• Subjects: Atherosclerosis -- Inflammation -- Leucocytes -- Transcription factors; Apoe Apolipoprotein E -- WD Western Diet -- MΦ Macrophages -- PLN Peripheral Lymph Node; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.08.045
• Languages: English
• ISSNs: 0021-9150

Abstract

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.