Karikó Katalin, Weissman Drew, Welsh Frank A
Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
J Cereb Blood Flow Metab. 2004 Nov;24(11):1288-304. doi: 10.1097/01.WCB.0000145666.68576.71.
Cerebral ischemia triggers acute inflammation, which exacerbates primary brain damage. Activation of the innate immune system is an important component of this inflammatory response. Inflammation occurs through the action of proinflammatory cytokines, such as TNF, IL-1 beta and IL-6, that alter blood flow and increase vascular permeability, thus leading to secondary ischemia and accumulation of immune cells in the brain. Production of these cytokines is initiated by signaling through Toll-like receptors (TLRs) that recognize host-derived molecules released from injured tissues and cells. Recently, great strides have been made in understanding the regulation of the innate immune system, particularly the signaling mechanisms of TLRs. Negative feedback inhibitors of TLRs and inflammatory cytokines have now been identified and characterized. It is also evident that lipid rafts exist in membranes and play a role in receptor-mediated inflammatory signaling events. In the present review, using this newly available large body of knowledge, we take a fresh look at studies of ischemic tolerance. Based on this analysis, we recognize a striking similarity between ischemic tolerance and endotoxin tolerance, an immune suppressive state characterized by hyporesponsiveness to lipopolysaccharide (LPS). In view of this analogy, and considering recent discoveries related to molecular mechanisms of endotoxin tolerance, we postulate that inhibition of TLR and proinflammatory cytokine signaling contributes critically to ischemic tolerance in the brain and other organs. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Tolerance can be established with two temporal profiles: (i) a rapid form in which the trigger induces tolerance to ischemia within minutes and (ii) a delayed form in which development of protection takes several hours or days and requires de-novo protein synthesis. The rapid form of tolerance is achieved by direct interference with membrane fluidity, causing disruption of lipid rafts leading to inhibition of TLR/cytokine signaling pathways. In the delayed form of tolerance, the preconditioning stimulus first triggers the TLR/cytokine inflammatory pathways, leading not only to inflammation but also to simultaneous upregulation of feedback inhibitors of inflammation. These inhibitors, which include signaling inhibitors, decoy receptors, and anti-inflammatory cytokines, reduce the inflammatory response to a subsequent episode of ischemia. This novel interpretation of the molecular mechanism of ischemic tolerance highlights new avenues for future investigation into the prevention and treatment of stroke and related diseases.
脑缺血引发急性炎症，这会加剧原发性脑损伤。固有免疫系统的激活是这种炎症反应的一个重要组成部分。炎症通过促炎细胞因子（如肿瘤坏死因子、白细胞介素 -1β和白细胞介素 -6）的作用而发生，这些细胞因子会改变血流并增加血管通透性，从而导致继发性缺血以及免疫细胞在脑内的积聚。这些细胞因子的产生是由通过Toll样受体（TLRs）的信号传导引发的，Toll样受体可识别从受损组织和细胞释放的宿主衍生分子。最近，在理解固有免疫系统的调节，尤其是Toll样受体的信号传导机制方面取得了很大进展。现在已经鉴定并表征了Toll样受体和炎性细胞因子的负反馈抑制剂。同样明显的是，脂筏存在于细胞膜中，并在受体介导的炎症信号事件中发挥作用。在本综述中，利用这些新获得的大量知识，我们重新审视了缺血耐受的研究。基于此分析，我们认识到缺血耐受与内毒素耐受之间存在惊人的相似性，内毒素耐受是一种以对脂多糖（LPS）反应低下为特征的免疫抑制状态。鉴于这种类比，并考虑到与内毒素耐受分子机制相关的最新发现，我们推测抑制Toll样受体和促炎细胞因子信号传导对脑和其他器官的缺血耐受起着关键作用。缺血耐受是一种由多种预处理刺激诱导的保护机制。耐受可以通过两种时间模式建立：（i）快速形式，其中触发因素在几分钟内诱导对缺血的耐受；（ii）延迟形式，其中保护作用的发展需要数小时或数天，并且需要重新合成蛋白质。快速形式的耐受是通过直接干扰膜流动性来实现的，导致脂筏破坏，从而抑制Toll样受体/细胞因子信号通路。在延迟形式的耐受中，预处理刺激首先触发Toll样受体/细胞因子炎症通路，不仅导致炎症，还会同时上调炎症的反馈抑制剂。这些抑制剂包括信号抑制剂、诱饵受体和抗炎细胞因子，可减少对随后缺血发作的炎症反应。这种对缺血耐受分子机制的新解释为未来中风及相关疾病的预防和治疗研究开辟了新途径。
