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

动脉粥样硬化是一种慢性炎症性疾病，其临床并发症包括心肌梗塞(MI) 和中风，是全球主要的死亡原因。鉴于令人信服的证据表明炎症是 在动脉粥样硬化的发展中的作用，预期是降脂，结合全球抑制 炎症，将显著减少晚期疾病的并发症。CANTOS的临床试验测试和 IL1抗体Canakinumab提供了令人信服的证据，证实了炎症假说。然而， 该药物未能获得FDA的批准，因为它的益处不大，包括不会减少心血管疾病 死亡(CVD)，但由于致命性感染死亡增加了40%。《诗篇》成绩令人失望的原因 是复杂的，但可能部分是由于IL1β抗体治疗抑制了有害的促炎作用 反应，但也进化保守的有益的炎症过程是损伤修复所必需的，包括 ACTA2+纤维帽的形成和维持。与这种可能性一致，我们(Gomez等人，2018年《自然》 医学)先前表明，在平滑肌细胞(SMC)的投资中需要IL1受体信号 和在保护性纤维帽中的滞留，以及晚期药物治疗SMC谱系追踪APOE/-小鼠 用小鼠白介素1抗体损伤8周后，可产生多种有害影响，包括 纤维帽内的SMC数和胶原含量。我们的研究只是众多例子中的一个 促炎信号在动脉粥样硬化的发病机制中可能起到有利或不利的作用。AS 因此，有必要确定更微妙的方法来抑制慢性炎症的不利影响 在不消除组织修复、对病原体的免疫抵抗力和炎症所必需的有益功能的情况下 决议。这项提议中的研究将检验选择性抑制白细胞介素6(IL-6)反式信号转导的假设 单独使用，而不是同时抑制反式和经典的白介素6受体(IL-6R)信号，不仅是避免 免疫缺陷，但也需要看到最佳的动脉粥样硬化保护效果，因为抵消 抑制IL-6反式信号的有利作用与抑制经典IL-6R信号的不利影响。我们 我将对这一假设进行如下检验。目标1将确定抑制两者的IL-6和IL-6R中和抗体 IL-6经典和反式信号转导，而IL6/sIL-6R陷阱sgp130Fc仅选择性抑制IL-6反式信号转导 信号，以不同的方式改变病变的发展或发病机制，包括细胞基质组成和指数 稳定性。我们将在我们的新型SMC-内皮细胞(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-/-小鼠，这些小鼠发展为晚期冠状动脉粥样硬化 以及自发性心肌梗塞的证据。目标2将明确IL-6反式信号在EC和SMC中在动脉粥样硬化中的作用 发展和晚期病变的发病机制。我们的方法将是选择性地消除IL-6反式信号转导 这些细胞通过EC或SMC特异性敲除(KO)的IL-6细胞因子家族信号转导糖蛋白130 (Gp130)(人类中的IL6ST)是在不表达IL-6R的EC和SMC等细胞中传递IL-6信号所需的。

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.