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: Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.08.045
• Languages: English
• ISSNs: 0021-9150

Abstract

<abstract xml:lang="en" abstract-type="author" id="abs0010"> <title id="sectitle0010">Abstract</title> <sec> <p id="abspara0010">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 <italic>Stat4</italic><sup><italic>−/−</italic></sup><italic>Apoe</italic><sup><italic>−/−</italic></sup> vs <italic>Apoe</italic><sup><italic>−/−</italic></sup> mice fed chow diet and significantly attenuated atherosclerosis (∼31%, p < 0.01) in western diet fed <italic>Stat4</italic><sup><italic>−/−</italic></sup><italic>Apoe</italic><sup><italic>−/−</italic></sup> mice. Surprisingly, reduced atherogenesis in <italic>Stat4</italic><sup><italic>−/−</italic></sup><italic>Apoe</italic><sup><italic>−/−</italic></sup> mice was not due to attenuated IFNγ production <italic>in vivo</italic> 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). <italic>Stat4</italic><sup><italic>−/−</italic></sup><italic>Apoe</italic><sup><italic>−/−</italic></sup><italic>in vitro</italic> differentiated M1 or M2 MΦs had reduced cytokine production compare to <italic>Apoe</italic><sup><italic>−/−</italic></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. <italic>Stat4</italic><sup><italic>−/−</italic></sup><italic>Apoe</italic><sup><italic>−/−</italic></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 <italic>Stat4</italic><sup><italic>−/−</italic></sup><italic>Apoe</italic><sup><italic>−/−</italic></sup> vs <italic>Apoe</italic><sup><italic>−/−</italic></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.</p> </sec> </abstract>