STAT4 deficiency reduces the development of atherosclerosis in mice

Parésa L. Taghavie-Moghadam, Breanne N. Gjurich, Rukhsana Jabeen, Purna Krishnamurthy, Mark H. Kaplan, Anca D. Dobrian, Jerry L. Nadler, Elena V. Galkina

Research output: Contribution to journalArticle

2 Scopus citations

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<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 languageEnglish (US)
Pages (from-to)169-178
Number of pages10
JournalAtherosclerosis
Volume243
Issue number1
DOIs
StatePublished - Nov 1 2015

Keywords

  • Atherosclerosis
  • Inflammation
  • Leucocytes
  • Transcription factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Taghavie-Moghadam, P. L., Gjurich, B. N., Jabeen, R., Krishnamurthy, P., Kaplan, M. H., Dobrian, A. D., Nadler, J. L., & Galkina, E. V. (2015). STAT4 deficiency reduces the development of atherosclerosis in mice. Atherosclerosis, 243(1), 169-178. https://doi.org/10.1016/j.atherosclerosis.2015.08.045