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，但没有特定的治疗方法。在出血部位先天免疫系统的激活导致单核细胞募集到大脑和进行性损伤。在脑出血小鼠模型中，PI已经证明血源性炎症单核细胞在脑出血后的第一天向血肿周围区域募集会导致明显的损伤。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反应的调节可能发生在外周，而单核细胞正在循环，尚未进入大脑。这种情况是否发生在脑出血尚不清楚。在其他模型中，细胞因子和生长因子的启动决定了单核细胞在炎症环境下是否会产生与吞噬和修复相关的M1、促炎反应或M2反应。我们提出了一个新的假设，即单核细胞对脑出血的反应可以在体循环中被调节，以减少早期炎症引起的损伤并加快恢复阶段。拟议的R21奖研究直接来自于这项临床前工作。我们将考察人类启动效应的影响

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.