Molecular mechanisms of LPS preconditioning in stroke

中风前系统给予小剂量的脂多糖（LPS）可以诱导神经保护，防止中风损伤，这一过程被称为LPS预处理或耐受。因此，对lps诱导的预处理的研究为确定新的介质提供了希望，这些介质可以系统地给予中枢神经保护。本应用程序的主要目的是研究脑卒中中的LPS预处理，并定义特定的分子途径，以辅助这种神经保护过程。初步数据表明，LPS预处理导致损伤缺血性脑的细胞浸润减少，细胞活化受到抑制，这表明LPS预处理改变了细胞对后续损伤刺激的反应性。低剂量LPS处理巨噬细胞使巨噬细胞通过改变促炎/抗炎介质的平衡，即基因组“重编程”，从而抵抗随后的高剂量LPS攻击的损伤。本提案的实验将研究LPS预处理是否通过重编程对损伤的反应，使其远离细胞死亡，有利于细胞存活，从而对随后的缺血性损伤提供保护。tnf - α是脂多糖预处理的重要介质，并可能启动导致中风后保护的事件。我们中风后的初步数据表明，与未接受LPS治疗的动物相比，先前接受LPS治疗的动物大脑中有额外的、独特的通路被诱导。在中风前给予LPS治疗的动物中，干扰素相关基因是独特基因上调的主要特征。我们假设tnf - α和I型ifn在LPS预处理中发挥重要的非重叠作用，导致神经保护。我们假设lps诱导的tnf - α通过重新编程细胞对随后缺血的反应，从损伤和细胞死亡转变为存活，从而启动耐受性的出现。随后，由1型ifn调节的通路被激活，从而赋予神经保护作用。通过体内和体外缺血耐受模型，我们提出：1)阐明tnf - α信号在LPS预处理后启动神经保护事件中的作用；2)确定I型IFNs是否在LPS预处理小鼠缺血性损伤后神经保护状态的建立中起关键作用；3)测试LPS预处理是否会导致缺血损伤反应的基因组重编程。这些研究将有助于阐明内源性LPS诱导的神经保护介质，并可能最终产生新的卒中治疗策略。

Neuroprotection against stroke injury can be induced by a small dose of lipopolysaccharide (LPS) given systemically prior to a stroke-a process known as LPS preconditioning or tolerance. As such, the study of LPS-induced preconditioning offers promise in identifying new mediators that can be administered systemically to confer neuroprotection centrally. The primary goal of this application is to investigate LPS preconditioning in stroke and define the specific molecular pathways that sub serve this neuroprotective process. Preliminary data suggest that LPS preconditioning leads to decreased cellular infiltration into the injured ischemic brain and suppressed cellular activation, which suggests that LPS preconditioning alters cellular responsiveness to subsequent injurious stimuli. Low dose LPS treatment of macrophages renders them resistant to the damage of subsequent high dose LPS challenge via a shift in the balance of proinflammatory/anti-inflammatory mediators referred to as genomic 'reprogramming'. Experiments in this proposal shall examine whether LPS preconditioning confers protection to subsequent ischemic injury by reprogramming the response to injury away from cell death and in favor of cell survival. TNF-alpha is an essential mediator in LPS preconditioning and may prime the events that lead to protection following stroke. Our preliminary data following stroke indicate that additional, unique pathways are induced in the brains of animals given prior LPS treatment compared to those not so treated. Interferon-associated genes are a dominant feature among the unique genes upregulated in animals given LPS treatment prior to a stroke. We hypothesize that TNF-alpha and Type I IFNs play essential, non-overlapping roles that lead to neuroprotection in LPS preconditioning. We postulate that LPS-induced TNF-alpha primes the emergence of tolerance by reprogramming the cellular response to subsequent ischemia from one of injury and cell death to that of survival. Subsequently, pathways regulated by Type 1 IFNs are activated which confer neuroprotection. Using in vivo and in vitro models of ischemic tolerance we propose to: 1) Elucidate the role of TNF-alpha signaling in priming the neuroprotective events following LPS preconditioning; 2) Determine whether Type I IFNs play a critical role in establishing a neuroprotective state following ischemic injury in LPS preconditioned mice; and 3) Test whether LPS preconditioning leads to genomic reprogramming of the response to ischemic injury. These studies should help clarify the endogenous mediators of neuroprotection induced by LPS and may ultimately lead to new therapeutic strategies for stroke.