Arteriosclerosis and its complications are the leading cause of morbidity and mortality in Western Societies. The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can be viewed, in aggregate, as an inflammatory disease process. Experimental, pathologic, and clinical observations support an essential role for CD4+ T cells in atherogenesis. Recent studies have shown a critical role for CD4+CD25+ T regulatory cells for inhibiting the progression of atherosclerosis, an effect dependent in part on TGF-2 signaling. However, the mechanisms underlying the acquisition of a T regulatory cell phenotype remain poorly understood. We have identified a member of the Krupple-like family of zinc finger class of transcription factors termed KLF10 as highly expressed in T regulatory cells expressing the forkhead transcription factor Foxp3, the most specific marker for cells that possess T regulatory suppressive function. KLF10 is robustly induced in CD4+CD25- cells in response to TGF-2 treatment and decreased by pro-inflammatory stimuli in response to T cell receptor activation. Consistently, KLF10 expression is reduced in spleens of atherosclerotic-prone ApoE-deficient mice. Overexpression of KLF10 in CD4+CD25- cells potently induced the T regulatory cell functional marker Foxp3 and suppressed co- cultured CD4+CD25- effector cells. In contrast, KLF10 potently inhibits pro- inflammatory T cell signaling responses mediated by activated NFAT1 (NFATc2). These observations have led us to the central hypothesis that KLF10 serves as a critical modulator of T regulatory function and atherosclerosis.
In AIM1 of this proposal we explore the mechanistic basis for KLF10's ability to induce Foxp3 gene expression.
In AIM2, we examine the ability of KLF10 to inhibit T cell receptor signaling events through NFAT1. Finally, in AIM3, we assess the consequences of KLF10 deficiency on the development of atherosclerosis and on T regulatory cell function. These studies will provide important insights regarding the role of KLF10 in T regulatory cell biology. The results of these studies are of considerable scientific interest and may serve as the basis for novel therapeutic strategies to suppress T cell activation, atherosclerosis, and autoimmune diseases.
The accumulation in the vessel wall of specific types of immune cells termed, T lymphocytes, is a characteristic feature seen in atherosclerosis (and other chronic inflammatory diseases), an effect that may promote disease progression leading to heart attack, stroke, or peripheral vascular disease. We have identified a novel gene, termed KLF10, that is highly expressed in cells that dampen the inflammatory response, called T regulatory cells, and our studies indicate that KLF10 may act to promote T regulatory cell function. The experiments proposed in this study will examine in detail the mechanisms by which KLF10 induces the T regulatory cell suppressive phenotype and its role in experimental atherosclerosis in vivo.
|Sun, Xinghui; Sit, Alan; Feinberg, Mark W (2014) Role of miR-181 family in regulating vascular inflammation and immunity. Trends Cardiovasc Med 24:105-12|
|Sun, Xinghui; He, Shaolin; Wara, A K M et al. (2014) Systemic delivery of microRNA-181b inhibits nuclear factor-?B activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice. Circ Res 114:32-40|
|Icli, Basak; Dorbala, Pranav; Feinberg, Mark W (2014) An emerging role for the miR-26 family in cardiovascular disease. Trends Cardiovasc Med 24:241-8|
|Feinberg, Mark W (2013) OutFOXing myeloid cells in atherosclerosis with FoxOs. Circ Res 112:978-82|
|Wara, Akm Khyrul; Manica, Andre; Marchini, Julio F et al. (2013) Bone marrow-derived Kruppel-like factor 10 controls reendothelialization in response to arterial injury. Arterioscler Thromb Vasc Biol 33:1552-60|
|Sun, Xinghui; Belkin, Nathan; Feinberg, Mark W (2013) Endothelial microRNAs and atherosclerosis. Curr Atheroscler Rep 15:372|
|Icli, Basak; Wara, A K M; Moslehi, Javid et al. (2013) MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling. Circ Res 113:1231-41|
|Sun, Xinghui; Icli, Basak; Wara, Akm Khyrul et al. (2012) MicroRNA-181b regulates NF-?B-mediated vascular inflammation. J Clin Invest 122:1973-90|
|Sun, Xinghui; Feinberg, Mark W (2012) Knocking out viral myocarditis: reality or a miRage? Circ Res 111:388-91|
|Sun, Xinghui; Feinberg, Mark W (2012) NF-?B and hypoxia: a double-edged sword in atherosclerosis. Am J Pathol 181:1513-7|
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