STAT4 deficiency reduces the development of atherosclerosis in mice

Atherosclerosis. 2015 Nov;243(1):169-78. doi: 10.1016/j.atherosclerosis.2015.08.045. Epub 2015 Sep 4.


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.

Keywords: Atherosclerosis; Inflammation; Leucocytes; Transcription factors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Aorta / pathology
  • Atherosclerosis / genetics*
  • B7-2 Antigen / metabolism
  • Bone Marrow Cells / cytology
  • Cell Differentiation
  • Cell Movement
  • Cytokines / metabolism
  • Female
  • Flow Cytometry
  • Inflammation
  • Interferon-gamma / metabolism*
  • Lectins, C-Type / metabolism
  • Lipids / blood
  • Macrophages / cytology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plaque, Atherosclerotic / genetics*
  • Real-Time Polymerase Chain Reaction
  • STAT4 Transcription Factor / genetics*
  • Th1 Cells / cytology*


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • B7-2 Antigen
  • CD69 antigen
  • Cd86 protein, mouse
  • Cytokines
  • Lectins, C-Type
  • Lipids
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Interferon-gamma