Role of IL-6 trans signaling in atherosclerosis development and late-stage pathogenesis

IL-6反式信号传导在动脉粥样硬化发展和晚期发病机制中的作用

• 批准号: 10652788
• 负责人: Gary K Owens
• 金额: $ 80.59万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652788
• 关键词: Acute; Adrenal Cortex Hormones; Adverse effects; Age; Agreement; Anti-Inflammatory Agents; Antibodies; Antibody Therapy; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Cardiovascular system; Cause of Death; Cell Count; Cell Lineage; Cell Separation; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Collagen; Complex; Coronary artery; Coxibs; Development; Diet; Disease; Disease Progression; Dose; Endothelial Cells; Event; Failure; Family; Fc Receptor; Frequencies; Human; IL-6 inhibitor; IL6 gene; IL6ST gene; Immune; Immunocompetence; Immunocompromised Host; Immunologic Deficiency Syndromes; Impairment; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin 6 Receptor; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-6; Intervention Studies; Investments; Knock-out; LDL Cholesterol Lipoproteins; Lesion; Lesion by Stage; Lipids; Macrophage; Maintenance; Mediator; Medicine; Methods; Methotrexate; Mus; Myocardial Infarction; Nature; PTPRC gene; Paper; Pathogenesis; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Play; Prevention; Probability; Process; Receptor Signaling; Resistance to infection; Resolution; Role; Rupture; Safety; Secondary to; Signal Transduction; Smooth Muscle Myocytes; Stroke; Tamoxifen; Testing; Transducers; United States; blood lipid; cell type; chronic inflammatory disease; cytokine; expectation; feeding; glycoprotein 130; high risk; immune resistance; indexing; inhibitor; injury and repair; insight; mouse model; multiplexed imaging; neutralizing antibody; novel; older patient; pathogen; patient population; primary endpoint; protective effect; response; systemic inflammatory response; therapeutically effective; tissue injury; tissue repair; western diet

Atherosclerosis is a chronic inflammatory disease whose clinical complications, including myocardial infarction (MI) and stroke, are the leading causes of death worldwide. Given the compelling evidence that inflammation plays a key role in development of atherosclerosis, the expectation was that lipid lowering, combined with global suppression of inflammation, would markedly reduce late-stage disease complications. The CANTOS clinical trial testing an IL1 antibody, Canakinumab, provided compelling evidence validating the inflammation hypothesis. However, the drug failed to get FDA approval due to it having modest beneficial effects including no reduction in cardiovascular death (CVD) but a 40% increase in death due to lethal infection. The reasons for the disappointing results of CANTOS are complex but likely were due in part to IL1β antibody treatment inhibiting not only detrimental pro-inflammatory responses, but also evolutionarily conserved beneficial inflammatory processes necessary for injury-repair including formation and maintenance of the ACTA2+ fibrous cap. Consistent with this possibility, we (Gomez et al., 2018 Nature Medicine) previously showed that IL1 receptor signaling in smooth muscle cells (SMC) is required for their investment and retention in the protective fibrous cap, and that treatment of SMC lineage tracing Apoe-/- mice with advanced lesions for 8-weeks with a murine IL1 antibody resulted in multiple detrimental effects including a >50% reduction in SMC number and collagen content within the fibrous cap. Our study is just one of many examples illustrating how pro-inflammatory signaling may have beneficial or detrimental effects on the pathogenesis of atherosclerosis. As such, there is a need to identify more nuanced approaches for inhibiting the adverse effects of chronic inflammation without eliminating beneficial functions essential for tissue repair, immune resistance to pathogens, and inflammation resolution. Studies in this proposal will test the hypothesis that selective inhibition of interleukin 6 (IL-6) trans signaling alone, rather than inhibition of both trans and classic IL-6 receptor (IL-6R) signaling, is not only preferred to avoid immuno-deficiencies, but is also required to see optimal atherosclerosis-protective effects because of offsetting beneficial effects of inhibiting IL-6 trans signaling versus detrimental effects of inhibiting classical IL-6R signaling. We will test this hypothesis as follows. Aim 1 will determine if IL-6 and IL-6R neutralizing antibodies, which inhibit both IL-6 classic and trans signaling, versus the IL6/sIL-6R trap sgp130Fc, which selectively inhibits only IL-6 trans signaling, differentially alter lesion development or pathogenesis including cell-matrix composition and indices of stability. We will do prevention and late stage intervention studies in our novel SMC-endothelial cell (EC) dual lineage tracing Apoe-/-mice, as well as our novel delta CT Ldlr-/-mice which develop advanced coronary artery atherosclerosis and evidence of spontaneous MI. Aim 2 will define the role of IL-6 trans signaling in EC and SMC in atherosclerosis development and late-stage lesion pathogenesis. Our approach will be to selectively eliminate IL-6 trans signaling in these cells by EC- or SMC-specific knock out (KO) of the IL-6 cytokine family signal transducer glycoprotein 130 (gp130) (IL6ST in humans) required for IL-6 signaling in cells like EC and SMC that do not express the IL-6R.

动脉粥样硬化是一种慢性炎性疾病，其临床并发症，包括心肌梗塞（MI） 和中风，是全球死亡的主要原因。鉴于令人信服的证据表明炎症起着关键 在动脉粥样硬化的发展中的作用，期望是降低脂质，加上全球抑制 炎症会显着减少晚期疾病并发症。 Cantos临床试验测试 IL1抗体canakinumab提供了令人信服的证据，以验证炎症假说。但是， 药物由于具有适度的有益作用，因此无法获得FDA批准 死亡（CVD），但由于致死感染而导致的死亡增加了40％。 Cantos令人失望的结果的原因 很复杂，但可能部分归因于IL1β抗体的治疗，不仅抑制了促炎性促进性 反应，但也有进化保守的有益炎症过程，需要 Acta2+纤维帽的形成和维护。与这种可能性一致，我们（Gomez等，2018自然 医学）先前表明，其投资需要平滑肌细胞中的IL1接收器信号传导（SMC） 并保留在受保护的纤维帽中，并使用先进的SMC谱系跟踪APOE - / - 带有鼠IL1抗体的8周的病变导致多种有害作用，包括降低> 50％ 纤维帽中的SMC编号和胶原蛋白含量。我们的研究只是众多示例之一，说明了如何 促炎的信号传导可能对动脉粥样硬化的发病机理具有有益或有害的影响。 这样，有必要确定更多细微的方法来抑制慢性感染的不良影响 不消除对组织修复必不可少的有益功能，对病原体的免疫力和炎症 解决。该提案中的研究将检验以下假设，即选择性抑制白介素6（IL-6）反式信号传导 单独使用，而不是抑制反式和经典的IL-6受体（IL-6R）信号传导，不仅是避免的 免疫缺陷，但还需要看到最佳的动脉粥样硬化保护作用 抑制IL-6反式信号传导与抑制经典IL-6R信号传导的有害作用的有益作用。我们 将测试该假设如下。 AIM 1将确定IL-6和IL-6R是否中和抗体，这两者都抑制 IL-6经典和反式信号，与IL6/SIL-6R陷阱SGP130FC相比，它仅有选择地抑制IL-6 Trans 信号传导，不同的改变病变发育或发病机理，包括细胞 - 矩阵组成和指标 稳定。我们将在新型的SMC-粘层细胞（EC）双重谱系中进行预防和后期干预研究 追踪Apoe - / - 小鼠，以及我们的新型Delta Ct LDLR - / - 鼠标，该小鼠会发展出晚期冠状动脉粥样硬化 以及赞助MI的证据。 AIM 2将定义IL-6反式信号在EC和SMC中的作用 发育和晚期病变发病机理。我们的方法是选择性地消除IL-6反式信号传导 这些细胞通过IL-6细胞因子家族信号传感器糖蛋白130的EC或SMC特异性敲除（KO） （GP130）（人类中的IL6ST）在不表达IL-6R的EC和SMC等细胞中IL-6信号传导所需。