title: STAT4 deficiency reduces the development of atherosclerosis in mice.
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.
authors.affiliation: Dept. of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Parésa L
authors.initials: PL
authors.lastname: Taghavie-Moghadam
authors.affiliation: Dept. of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Breanne N
authors.initials: BN
authors.lastname: Gjurich
authors.affiliation: Dept. of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Jabeen
authors.affiliation: Dept. of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Purna
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: Dept. of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.affiliation: Dept. of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Anca D
authors.initials: AD
authors.lastname: Dobrian
authors.affiliation: Dept. of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.affiliation: Dept. of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA. Electronic address: galkinev@evms.edu.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Galkina
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics*; D051940:B7-2 Antigen / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000235:genetics*; D018417:Th1 Cells / Q000166:cytology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051940:B7-2 Antigen; D016207:Cytokines; D007371:Interferon-gamma; D037181:Lectins, C-Type; D008055:Lipids; D050797:STAT4 Transcription Factor; D000099192:CD69 Antigens; C497965:Cd86 protein, mouse; C494091:Stat4 protein, mouse
keywords: Atherosclerosis; Inflammation; Leucocytes; Transcription factors