Platelets in radiation-induced immune dysregulation

研究综述 在大规模核事件中，许多人可能暴露在高剂量的电离辐射(IR)中。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，并导致 依赖于功能免疫系统的器官功能障碍。目前还没有FDA批准的药物 可用于缓解辐射受害者的免疫失调。该项目的总体目标是 了解暴露于IR后，血小板如何导致免疫失调，并检测以血小板为中心的 减轻IR诱导的免疫失调和器官损伤(特别是肠道损伤)的对策 和心)。血小板可以通过直接与免疫细胞结合或通过运送亚微米颗粒来调节免疫功能。 血小板源微粒(PMPs)进入细胞。在每个健康的个体中，血小板形成血小板-白细胞 在正常情况下，在循环中聚集和产生PMP，但这些活动在 病理情况。不同的血小板受体与其在白细胞上的特异性对应物受体相互作用， 特别是中性粒细胞(PMN)和单核细胞--天然免疫的两个重要成员 可以改变适应性免疫反应的系统--形成血小板-白细胞聚集体。这是关键所在 相互作用是血小板膜糖蛋白Ibα(GPIBα)与白细胞Mac-1结合，导致两个血小板的激活 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，蛋白水解性裂解血小板GPVI是产生PMP的关键步骤。我们的初步数据显示 患有功能障碍的GPIBα(不能结合Mac-1)的小鼠表现出更多的炎症，肠道损伤，PMP 与野生型小鼠相比，单次8.5Gy体照射(TBI)后的小鼠死亡率、世代数和致死率都有所下降。 此外，我们发现具有功能障碍的gpibα的小鼠在服用多菌素后更容易发生炎症。 败血症，暴露于红外线后可能发生。最后，GPVI-KO小鼠产生的PMP更少，表现为减少 8.5GyTBI后血浆促炎细胞因子水平与GPIBα功能障碍小鼠的比较。我们 假设缺乏GPIBα-Mac-1相互作用和增强的PMP生成有助于IR的诱导 免疫失调和预测，服用外源性GPIBα或限制PMP产生将缓解 IR引起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的结合是否加剧，同时外源性GPIBα管理 缓解脑损伤诱导的免疫失调，以及2)评估是否通过抑制PMP的产生来限制PMP的产生 GPVI可减轻脑外伤所致的免疫失调。我们的研究将为我们提供对以前 血小板-白细胞相互作用和PMP生成在调节IR诱导免疫中的作用 监管失调。最重要的是，这些发现将有助于开发新型的辐射缓释剂。

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.