Role of IL1b in Regulating SMC and Macrophage Differentiation in Atherosclerosis

描述（由申请人提供）：动脉粥样硬化是一种慢性炎症性疾病，是发达国家发病率和死亡率的主要原因。然而，我们对其发展的潜在机制和终末期临床事件（包括可能的心肌梗死或中风的斑块破裂）的了解仍然存在根本性的差距。尽管该领域的教条是，病变内平滑肌细胞（SMC）与巨噬细胞比例的增加促进了斑块的稳定性，但该模型的实验证据存在重大局限性，包括病变内哪些细胞是SMC还是单核细胞-巨噬细胞起源，以及控制SMC和巨噬细胞数量和表型的机制存在重大歧见。重要的是，Owens实验室采用独特的SMC谱系追踪ApoE-/-小鼠进行的研究提供了证据，表明晚期病变中约25%的细胞是SMC-而不是巨噬细胞来源的，这些细胞是Mac2+，但SMC标记物（包括SM -肌动蛋白（SM - A））阴性。相反，很大一部分的sma +纤维帽细胞，被认为是smc衍生的，却不是。此外，我们有证据表明，相当一部分巨噬细胞来源的细胞显示巨噬细胞标志物表达减少，但SM - a +。综上所述，巨噬细胞可以转化为SMC样细胞，SMC也可以转化为巨噬细胞样细胞。此外，结果表明，很可能有很多

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease and is the leading cause of morbidity and death in developed countries. However, there are still fundamental gaps in our knowledge of the underlying mechanisms that contribute to its development, and end-stage clinical events including plaque rupture with possible myocardial infarction or stroke. Although the dogma in the field is that an increased ratio of smooth muscle cells (SMC) to macrophages within lesions promotes plaque stability, there are major limitations in the experimental evidence for this model including major ambiguities regarding which cells within lesions are of SMC versus monocyte-macrophage origin and the mechanisms that control SMC and macrophage number and phenotype. Of major significance, studies employing unique SMC lineage tracing ApoE-/- mice developed by the Owens lab provide evidence that ~25% of cells within advanced lesions that are Mac2+ but negative for SMC markers including SM �-actin (SM�A), are SMC- rather than macrophage-derived. Conversely, a significant fraction of SM�A+ fibrous cap cells, presumed to be SMC-derived, are not. Moreover, we have evidence in that a significant fraction of macrophage- derived cells show reduced macrophage marker expression but are SM�A+. Collectively, results show that macrophages may convert to SMC-like cells and SMC to macrophage-like cells. Moreover, results indicate that it is likely that many lesion cells have been mis-identified in previous studies in the field, thus greatly confounding our understanding of the mechanisms and factors that regulate phenotypic transitions of these cells. The central focus of this grant is to determine the effects of genetic or pharmacological inhibition of IL1� and IL1R1 signaling on phenotypic transitions of SMC and macrophages, as well as on the overall size and stability of late stage atherosclerotic lesions. Whereas there is good evidence that disruption of IL1� signaling inhibits formation of fatty streaks and early stage lesions, the role of IL1 in late stage lesions is unclear. Aim 1a will use novel utilize SMC and myeloid specific lineage tracing IL1R1 knockout mouse lines generated by our lab to test the hypothesis that IL1R1-dependent transitions in phenotype of SMC and macrophages within advanced atherosclerotic lesions play a critical role in determining overall plaque and lumen size, as well as lesion composition including multiple indices of plaque stability. Aim 1b will be o determine if phenotypic transitions observed in our mouse studies occur in human atherosclerotic lesions based on analysis of autopsy specimens using a highly novel epigenetic SMC lineage tracing method recently developed by our laboratory (Gomez et al., Nature Methods). Aim 2 will determine if treatment of ApoE null mice with a Novartis mouse anti-IL1� antibody induces changes in lesion size, cellular composition, or indices of plaque stability, as well as transitions in SMC and/or macrophage phenotype.