Novel histone-binding C-type lectin receptors and their role in sterile inflammation and tissue injury

摘要 免疫系统已经进化出识别细胞损伤并作为回应刺激不孕的机制。 发炎。这种反应对健康和疾病都有重要的贡献。在这个过程中，死亡的细胞 释放免疫细胞上的受体检测到的损伤相关细胞模式(DAMP)，然后 引发无菌炎症。组蛋白是无菌炎症的主要驱动力，有一种 最近越来越多的文献表明，组蛋白的释放和对组蛋白的反应与糖尿病的发病率和死亡率有关 组织损伤。鉴于这些湿气在疾病发病机制中的作用，了解 与这些配体结合并调节其作用的受体。在我们的工作之前，这种受体是未知的。 我们发现了第一个组蛋白的细胞受体，即C型凝集素受体(CLR/CLEC)Clec2d。 我们发现，clec2d在组蛋白的先天免疫反应和发病机制中起着重要作用。 活体内的疾病。我们的研究还揭示了Clec2d并不是整个故事的全部，肯定还有另一个 小鼠体内的组蛋白受体(S)，参与反应和疾病。此外，人类先天免疫细胞 同样受到组蛋白的刺激，然而当我们将我们的发现翻译到人类身上时，我们发现 Clec2d的人类同源物不识别组蛋白。因此，目前尚有尚未确定的人类 组蛋白受体。重要的是，我们现在已经在两只小鼠身上发现了这种新的CLEC-组蛋白受体(CHR) 人类和这些发现构成了这项拨款申请的基础。我们有两个目标：目标1将 阐明CHRS在体内对组蛋白的先天免疫反应中的作用。我们将定义什么是先天免疫 细胞使用CHR来感觉体内的组蛋白，随后反应的性质，以及它们在不育中的作用 活体组织损伤的炎症反应和致病后遗症。这一目标的重要性在于它将 提供对疾病发病机制的洞察，并有可能确定治疗这些疾病的新分子靶点 并且，目标2将定义组蛋白的特异性、结果和潜在机制 刺激新的CHRS。这一目标的重要性在于，它将定义基本机制， 组蛋白及其受体触发和调节反应，最终推动宿主防御和 病理生物学。

Abstract The immune system has evolved mechanisms to recognize cell injury and in response stimulate sterile inflammation. This response contributes in important ways to both heath and disease. In this process, dying cells release Damage Associated Cell Patterns (DAMPs) that are detected by receptors on immune cells, which then trigger sterile inflammation. Histones are DAMPs that are major drivers of sterile inflammation and there is a recent growing literature implicating the release of and response to histones in the morbidity and mortality from tissue injury. Given the role of these DAMPs in the pathogenesis of disease, it is important to understand the receptors that engage these ligands and mediate their effects. Before our work, such receptors were unknown. We discovered the first cellular receptor for histones, which was the C-type lectin receptor (CLR/Clec) Clec2d. We showed that Clec2d plays an important role in innate immune responses to histones and the pathogenesis of disease in vivo. Our studies also revealed that Clec2d is not the whole story and that there must be another histone receptor(s) in mice that contributes to responses and disease. Moreover, human innate immune cells are similarly stimulated by histones, however when we went to translate our findings to humans, we found that the human homolog of Clec2d does not recognize histones. Therefore, there are as yet to be identified human histone receptors. Importantly, we have now discovered such novel Clec-histone receptors (CHRs) in both mice and humans and these discoveries form the basis for this grant application. We have two Aims: Aim 1 will elucidate the role of CHRs in innate immune responses to histones in vivo. We will define what innate immune cells use CHRs to sense histones in vivo, the nature of the subsequent responses, and their role in the sterile inflammatory response and pathogenic sequelae of tissue injury in vivo. The importance of this aim is that it will provide insight into disease pathogenesis and potentially identify new molecular targets for treating these conditions; and, Aim 2 will define the specificity, consequences and underlying mechanisms of histone stimulation of novel CHRs. The importance of this aim is that it will define the underlying mechanisms by which histones and their receptors trigger and regulate responses, which ultimately drive host defense and pathobiology.