Protective monocytes in cerebral ischemic tolerance

描述（由申请人提供）：中风是一种高度流行和毁灭性的疾病，治疗选择有限。迄今为止，大多数开发中风治疗方法的努力在大型临床试验中取得了有限的成功。大脑具有巨大的自我保护能力，阐明大脑如何自我保护可能会为中风治疗提供新的见解。缺血耐受（Ischemic tolerance， IT）是亚致死应激预处理（PC）刺激的一种现象；诱发对随后的缺血损伤的耐受状态，是内源性神经保护的一个例子。全身给药toll样受体-4配体脂多糖（LPS）可诱导脑内IT。不同群体的免疫细胞可能在LPS诱导的PC中发挥作用。特别是单核细胞，作为LPS的主要靶点，可以直接或通过调节免疫系统发挥强大的保护作用。然而，单核细胞或其他免疫细胞是否在LPS诱导的it中起作用尚不清楚。鉴定负责LPS诱导的IT的细胞类型将是重要的，因为它将为基于这些保护性免疫细胞的缺血性卒中新疗法提供前景。该应用将验证LPS诱导保护性单核细胞在脑内的植入，从而直接或通过调节对脑缺血的免疫反应来改善缺血性脑损伤的假设。为此，我们将确定(a)神经保护性单核细胞亚型的起源，(b)驱动它们进入大脑的分子因素，以及(c)它们赋予神经保护的机制。此外，我们将确定这些细胞是否可以过继转移，以保护动物免受实验性中风的临床相关治疗窗口。这些目标将通过小鼠短暂局灶性脑缺血模型来实现，并评估组织学和神经学结果。LPS PC对免疫细胞群的影响将通过流式细胞术进行评估。

DESCRIPTION (provided by applicant): Stroke is a highly prevalent and devastating disease with limited therapeutic options. Most efforts to develop treatments for stroke have thus far met with limited success in large clinical trials. The brain has an enormous capacity for self-preservation, and elucidating how the brain protects itself may provide novel insights into stroke treatment. Ischemic tolerance (IT), a phenomenon in which application of sub-lethal stress [preconditioning (PC) stimulus; PC] induces a state of tolerance to a subsequent ischemic insult, represents an example of endogenous neuroprotection. IT can be induced in brain by systemic administration of the Toll-like receptor-4 ligand lipopolysaccharide (LPS). Different populations of immune cell could potentially play a role in PC induced by LPS. In particular, monocytes, which are the main target of LPS, can exert a powerful protective effect either directly or by modulating the immune system. However, it remains to be established whether monocytes or other immune cells play a role in the IT induced by LPS. The identification of the cell type(s) responsible for LPS induced IT would be important as it would offer the prospect of novel therapies for ischemic stroke based on these protective immune cells. This application will test the hypothesis that LPS PC induces brain engraftment of protective monocytic cells that ameliorate ischemic brain injury either directly or by modulating the immune response to cerebral ischemia. To this end, we will determine (a) the origin of neuroprotective monocytic subtypes, (b) the molecular factors driving their entry into the brain, and (c) the mechanisms by which they confer neuroprotection. Furthermore, we will determine whether these cells can be adoptively transferred to protect animals from experimental stroke with a clinically relevant therapeutic window. These goals will be achieved using a mouse model of transient focal cerebral ischemia with assessment of histological and neurological outcome. The effect of LPS PC on immune cell populations will be assessed by flow cytometry. PUBLIC HEALTH RELEVANCE: Stroke caused by insufficient blood flow to the brain (ischemic stroke) is a leading cause of brain damage and death, but there is a paucity of therapies to protect the brain from its devastating effects. Our studies will explore new ways to dampen stroke damage based on the body's own ability to protect the brain. In particular, we will examine whether certain immune cells (monocytes) can make the brain more tolerant to the lack of blood that causes the stroke. The findings offer the prospect of using these monocytes as a novel treatment for acute ischemic stroke.