STAT4 deficiency reduces the development of atherosclerosis in mice

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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
Article number14259
Pages (from-to)169-178
Number of pages10
JournalAtherosclerosis
Volume243
Issue number1
DOIs
StatePublished - Nov 1 2015

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STAT4 Transcription Factor
Apolipoproteins E
Atherosclerosis
Macrophages
Th1 Cells
T-Lymphocytes
Interleukin-12

Keywords

  • Atherosclerosis
  • Inflammation
  • Leucocytes
  • Transcription factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Taghavie-Moghadam, P. L., Gjurich, B. N., Jabeen, R., Krishnamurthy, P., Kaplan, M., Dobrian, A. D., ... Galkina, E. V. (2015). STAT4 deficiency reduces the development of atherosclerosis in mice. Atherosclerosis, 243(1), 169-178. [14259]. https://doi.org/10.1016/j.atherosclerosis.2015.08.045

STAT4 deficiency reduces the development of atherosclerosis in mice. / Taghavie-Moghadam, Parésa L.; Gjurich, Breanne N.; Jabeen, Rukhsana; Krishnamurthy, Purna; Kaplan, Mark; Dobrian, Anca D.; Nadler, Jerry L.; Galkina, Elena V.

In: Atherosclerosis, Vol. 243, No. 1, 14259, 01.11.2015, p. 169-178.

Research output: Contribution to journalArticle

Taghavie-Moghadam, PL, Gjurich, BN, Jabeen, R, Krishnamurthy, P, Kaplan, M, Dobrian, AD, Nadler, JL & Galkina, EV 2015, 'STAT4 deficiency reduces the development of atherosclerosis in mice', Atherosclerosis, vol. 243, no. 1, 14259, pp. 169-178. https://doi.org/10.1016/j.atherosclerosis.2015.08.045
Taghavie-Moghadam PL, Gjurich BN, Jabeen R, Krishnamurthy P, Kaplan M, Dobrian AD et al. STAT4 deficiency reduces the development of atherosclerosis in mice. Atherosclerosis. 2015 Nov 1;243(1):169-178. 14259. https://doi.org/10.1016/j.atherosclerosis.2015.08.045
Taghavie-Moghadam, Parésa L. ; Gjurich, Breanne N. ; Jabeen, Rukhsana ; Krishnamurthy, Purna ; Kaplan, Mark ; Dobrian, Anca D. ; Nadler, Jerry L. ; Galkina, Elena V. / STAT4 deficiency reduces the development of atherosclerosis in mice. In: Atherosclerosis. 2015 ; Vol. 243, No. 1. pp. 169-178.
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AU - Krishnamurthy, Purna

AU - Kaplan, Mark

AU - Dobrian, Anca D.

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