Platelets in radiation-induced immune dysregulation

研究综述 在大规模核事故中，许多人可能会受到高剂量的电离辐射（IR）。这可以 对免疫功能有长期的不利影响，使受害者面临免疫紊乱的风险， 依赖于免疫系统的器官功能失调。目前，FDA批准的药物 可以缓解辐射受害者的免疫失调。该项目的总体目标是 了解血小板如何在暴露于IR后促进免疫失调，并测试血小板中心 减轻IR诱导的免疫失调和器官损伤（特别是在肠中）的对策 心）。血小板可以通过直接与免疫细胞结合或通过亚微米递送来调节免疫功能。 血小板衍生的微粒（PMP）的细胞。在每个健康的个体中，血小板形成血小板-白细胞 在正常条件下，在循环中聚集并产生PMPs，但这些活动在 病理条件。各种血小板受体与它们在白细胞上的特异性反受体相互作用， 特别是多形核中性粒细胞（PMNs）和单核细胞-先天免疫系统的2个关键成员 系统，可以修改适应性免疫反应-形成血小板-白细胞聚集体。这方面的核心 相互作用是血小板糖蛋白Ibα（GPIbα）与白细胞Mac-1结合，导致两种血小板活化 和白细胞。PMPs可以通过递送细胞因子、生长因子和RNA来激活PMN和单核细胞。 值得注意的是，血小板GPVI的蛋白水解裂解是PMP生成的必要步骤。我们的初步数据显示 GPIbα功能障碍的小鼠（不能结合Mac-1）表现出炎症、肠损伤、PMP 代，以及与野生型小鼠相比，在单剂量8.5戈伊全身照射（TBI）后的致死率。 此外，我们发现，GPIbα功能障碍的小鼠在多微生物刺激后更容易发生炎症。 败血症，这可能发生在IR暴露后。最后，GPVI-KO小鼠产生更少的PMP，并且表现出降低的 血浆促炎细胞因子水平与8.5戈伊TBI后GPIbα功能障碍的小鼠相比。我们 假设缺乏GPIbα-Mac-1相互作用和PMP产生增强有助于IR诱导的 免疫失调和预测给予外源性GPIbα或限制PMP产生将减轻 IR诱导的免疫失调和器官损伤。本提案中概述的研究将：1）确定 选择性阻断GPIbα与Mac-1的结合是否加重，而外源性GPIbα给药 缓解TBI诱导的免疫失调，以及2）评价是否通过抑制 GPVI减轻TBI诱导的免疫失调。我们的研究将提供深入了解以前 血小板-白细胞相互作用和PMP产生在调节IR诱导的免疫中的作用尚未探索 失调最重要的是，这些发现将有助于开发新的辐射缓解剂。

RESEARCH SUMMARY In a large-scale nuclear event, many people could be exposed to high doses of ionizing radiation (IR). This can have long-term adverse effects on immune function, putting victims at risk for immune disorders and contributing to the dysfunction of organs that depend on a functional immune system. Currently no FDA-approved drugs are available to mitigate immune dysregulation in radiation victims. The overall objectives of this project are to understand how platelets contribute to immune dysregulation after exposure to IR and to test platelet-centric countermeasures to mitigate IR-induced immune dysregulation and organ damage (specifically in the intestine and heart). Platelets can regulate immune function by binding directly to immune cells or by delivering submicron platelet-derived microparticles (PMPs) to the cells. In every healthy individual, platelets form platelet–leukocyte aggregates and generate PMPs in the circulation under normal conditions, but these activities increase under pathological conditions. Various platelet receptors interact with their specific counter receptors on leukocytes, specifically polymorphonuclear neutrophils (PMNs) and monocytes—2 crucial members of the innate immune system that can modify the adaptive immune response—to form platelet–leukocyte aggregates. Central to this interaction is platelet glycoprotein Ibα (GPIbα) binding to leukocyte Mac-1, resulting in activation of both platelets and leukocytes. PMPs can activate PMNs and monocytes by delivering cytokines, growth factors, and RNA. Notably, proteolytic cleavage of platelet GPVI is an essential step for PMP generation. Our preliminary data show that mice with dysfunctional GPIbα (cannot bind Mac-1) exhibit increased inflammation, intestinal injury, PMP generation, and lethality following a single dose of 8.5 Gy total-body irradiation (TBI) compared to wild-type mice. Moreover, we showed that mice with dysfunctional GPIbα are more prone to inflammation following polymicrobial sepsis, which can occur after IR exposure. Finally, GPVI-KO mice generate fewer PMPs and exhibit reduced plasma pro-inflammatory cytokine levels compared to mice with dysfunctional GPIbα after 8.5 Gy TBI. We hypothesize that lack of GPIbα–Mac-1 interaction and enhanced PMP generation contribute to IR-induced immune dysregulation and predict that administering exogenous GPIbα or limiting PMP generation will mitigate IR-induced immune dysregulation and organ damage. The studies outlined in this proposal will: 1) Determine whether selective blocking of GPIbα binding to Mac-1 exacerbates, while exogenous GPIbα administration mitigates, TBI-induced immune dysregulation and 2) Evaluate whether limiting PMP generation by inhibiting GPVI mitigates TBI-induced immune dysregulation. Our studies will provide insight into the previously unexplored role of platelet–leukocyte interaction and PMP generation in modulating IR-induced immune dysregulation. Most importantly, the findings will help to develop novel radiation mitigators.