Modulating Monocyte Responses to Reduce Injury after Intracerebral Hemorrhage

描述（由申请人提供）：脑出血（ICH）是一种毁灭性的中风类型，每年影响全球200多万患者，但没有具体的治疗方法。出血部位先天免疫系统的激活导致单核细胞向脑募集和进行性损伤。在ICH的鼠模型中，PI已经证明，在ICH后的第一天，血液来源的炎性单核细胞向血肿周围区域的募集导致显著损伤。然而，随着时间的推移，这些细胞有助于吞噬和恢复。有趣的是，单核细胞对炎症刺激的反应的调节可能发生在外周，而单核细胞正在循环并且尚未进入大脑。这是否发生在ICH中尚不清楚。在其他模型中，由细胞因子和生长因子引发的启动决定单核细胞是否会发展M1、促炎反应或与吞噬相关的M2反应，并响应于炎症环境进行修复。我们提出了一个新的假设，即单核细胞对ICH的反应可以在体循环中进行调节，以最大限度地减少早期炎症诱导的损伤并加快恢复阶段。 拟议的R21奖研究直接遵循这项临床前工作。我们将研究人类启动的效果 在ICH患者的循环中升高的具有炎性细胞因子和生长因子的单核细胞对这些细胞对炎性刺激的效应器应答的影响。我们假设，与白细胞介素-4（IL-4）引发将导致增强的吞噬作用和减少的促炎介质（M2反应）的表达。这项工作将包括来自健康对照和ICH患者的单核细胞，以最大限度地提高翻译相关性。这代表了一种减少ICH后损伤的新策略，并将增加对穿过血脑屏障的潜在治疗的需求。这项探索性工作将确定调节单核细胞反应的治疗策略是否有可能改善ICH后的结局。

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a devastating type of stroke affecting more than 2 million patients worldwide each year, yet there is no specific treatment available. Activation of the innate immune system at the site of hemorrhage leads to monocyte recruitment to the brain and progressive injury. In a murine model of ICH, the PI has demonstrated that the recruitment of blood-derived inflammatory monocytes to the perihematomal region leads to significant injury in the first days after ICH. However, over time, these cells contribute to phagocytosis and recovery. Interestingly, modulation of monocyte responses to inflammatory stimuli may occur in the periphery, while the monocytes are circulating and have not yet entered the brain. Whether this occurs in ICH is not known. In other models, priming by cytokines and growth factors determine whether monocytes will develop M1, proinflammatory responses, or M2 responses associated with phagocytosis and repair in response to an inflammatory environment. We propose the novel hypothesis that monocyte responses to ICH can be modulated in the systemic circulation in order to minimize early, inflammation-induced injury and expedite the recovery phase. The proposed R21 Award studies follow directly from this pre-clinical work. We will examine the effect of priming of human monocytes with inflammatory cytokines and growth factors elevated in the circulation of ICH patients on the effector responses of those cells to an inflammatory stimulus. We hypothesize that priming with interleukin-4 (IL-4) will result in enhanced phagocytosis and reduced expression of pro-inflammatory mediators (M2 response). This work will include both monocytes from both healthy controls and patients with ICH in order to maximize translational relevance. This represents a novel strategy for reducing injury after ICH, and would obviate the need for a potential therapeutic to cross the blood-brain barrier. This exploratory work will determine whether therapeutic strategies that modulate monocyte responses have the potential to improve outcomes after ICH.