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

新型组蛋白结合 C 型凝集素受体及其在无菌炎症和组织损伤中的作用

• 批准号: 10566947
• 负责人: KENNETH L ROCK
• 金额: $ 59.39万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-09 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566947
• 关键词: Applications Grants; Automobile Driving; Binding; Biological; Biology; C Type Lectin Receptors; Cell Death; Cells; Communicable Diseases; DNA; Disease; Endosomes; Goals; Health; Histones; Homologous Gene; Host Defense; Human; Immune; Immune system; Infarction; Inflammation; Inflammatory Response; Injury; Innate Immune Response; Ischemia; Kidney; Ligands; Literature; Liver; Malignant Neoplasms; Mediating; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myocardial Infarction; Nature; Nucleosomes; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Play; Process; Receptor Signaling; Reperfusion Injury; Reperfusion Therapy; Role; Sepsis; Specificity; Sterility; Stroke; Testing; Tissues; Toll-like receptors; Translating; Trauma; Work; cell injury; extracellular; in vivo; insight; mortality; neutrophil; novel; prevent; receptor; receptor binding; receptor function; response; tissue injury

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.

抽象的 免疫系统已经进化出识别细胞损伤并刺激无菌的机制 炎。这种反应对健康和疾病都有重要影响。在这个过程中，死亡的细胞 释放由免疫细胞上的受体检测到的损伤相关细胞模式 (DAMP)，然后 引发无菌性炎症。组蛋白是 DAMP，是无菌性炎症的主要驱动因素，并且存在 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发病率和死亡率有关 组织损伤。鉴于这些 DAMP 在疾病发病机制中的作用，了解这些 DAMP 非常重要 与这些配体结合并介导其作用的受体。在我们的工作之前，此类受体是未知的。 我们发现了第一个组蛋白细胞受体，即 C 型凝集素受体 (CLR/Clec) Clec2d。 我们证明 Clec2d 在组蛋白的先天免疫反应及其发病机制中发挥重要作用 体内疾病的发生。我们的研究还表明，Clec2d 并不是故事的全部，一定还有另一个 小鼠体内有助于反应和疾病的组蛋白受体。此外，人类先天免疫细胞 类似地受到组蛋白的刺激，但是当我们将我们的发现转化为人类时，我们发现 Clec2d 的人类同源物不识别组蛋白。因此，目前尚无法确定人类 组蛋白受体。重要的是，我们现在在两只小鼠中发现了这种新型 Clec 组蛋白受体 (CHR) 人类和这些发现构成了本次拨款申请的基础。我们有两个目标：目标 1 将 阐明 CHR 在体内组蛋白先天免疫反应中的作用。我们将定义什么是先天免疫 细胞利用 CHR 来感知体内组蛋白、随后反应的性质及其在无菌中的作用 体内组织损伤的炎症反应和致病性后遗症。这一目标的重要性在于它将 提供对疾病发病机制的深入了解，并可能确定治疗这些疾病的新分子靶点 状况;并且，目标 2 将定义组蛋白的特异性、后果和潜在机制 刺激新的 CHR。这一目标的重要性在于，它将定义实现这一目标的基本机制。 组蛋白及其受体触发并调节反应，最终驱动宿主防御和 病理学。