Cerebral Ischemia Versus Microglia: More Than Just Inflammation

Objective: Local cerebral ischemia(cerebral ischemia, CI), with its high morbidity, mortality and disability, is harmful to human health seriously. So we tried to look for new therapeutic targets of CI from the pathological mechanism after CI.Methods: We look up a large number of SCI literatures about microglia and cerebral ischemia which are referenced in my paper.Results: Our previous studies have suggested that inflammation as the main source of damage, can cause nerve damage with other kinds of pathological mechanism together. We used a variety of means such as drugs or inhibitors to intervene in cerebral ischemia model, and found that with inflammation controlled, the damage of ischemia will relieve, on the contrary, with inflammation amplified, the harm will aggravate. Many research have indicated that the inflammatory factors such as IL-1β,TNF-α,IL-6,mainly come from microglia.In order to control inflammation, we turn focus on microglial cells. Surprisingly, however, we found that the role of microglia is not limited to the inflammatory response. As the central nervous system(CNS) immune cells, they play an key role in development, homeostasis and stress of CNS. Microglia are derived from primitive CD45-c-kit+ progenitors that emanate from the embryonic yolk sac during development,they turn to CD45+c-kit-CX3CR1+ microglia and enter the brain rudiment via the circulatory system. These progenitors surround the neuroepithelium of the developing brain and enter the neuroepithelium with the help of MMPs and begin to colonize the CNS parenchyma. With the down regulation of Runx1, microglia with an amoeboid morphology gradually develop into matureramified morphology. Development and survival of microglia are critically dependent on several factors, including the transcription factor PU.1, CSF1 R, Runx1, IRF-8 and mi R-124, etc. There is still a dispute that microglia renew from where. Microglia were proposed to be of hematopoietic origin. In recent years, many research have confirmed that no matter in physiological or pathological conditions, microglia proliferate by their mitosis, rather than the monocytes in circulation. Microglia are different from other tissue resident macrophages, they are independent relatively and irreplaceable, which benefit to maintain CNS immune privilege. In the normal adult CNS, there are many receptors on the membrane. Microglia have a complex morphology with highly ramified processes extending from a compact cell body that continuously scan the environment transiently contacting synapses as well extrasynaptic regions. The microglial processes directly appose not only presynaptic terminals, but also perisynaptic astrocytic clefts. In addition, microglia can secrete many trophic factors which are critical to the survival and function of neuron. During the development of CNS, microglia can secrete many trophic factors such as BDNF,GDNF,IGF-1,TGF-βto participate in the processes of neuron generation, synapsis maturity, and circuit formation. Microglia are not simply accessory cells that respond to neuronalcell death during development, but rather are active promoters of the process. They can remove the resultant cellular debris through phagocytosis. Noninflammatory microglial phagocytosis is mediated through signaling via triggering receptor expressed on myeloid cells-2. In addition to clearance of dead cells, microglial phagocytic activity is crucial for synaptic homeostasis. They can clean the useless excess synapses which go against the formation of circuit. This process called “Synaptic Pruning” is regulated by CSF1 signalling and is critical to neuron development. Microglia respond to almost all types of CNS injury by switching from a surveillance state to various types of activated(effector) phenotypes thatinclude rapid changes in cell morphology, gene expression, and function. Microglial activation is a highly regulated process that may result from either appearance of novel “on” signals(such as LPS, virus DNA or RNA, neoplasm component) or loss of restraining “off” signals(such as CD200 and CX3CL1). In normal conditions, these signals may be restricted to small subpopulations or even subcompartments of microglial cells. Upon activation, microglia switch from a ramified to an amoeboid appearance and actively move toward a lesion or a local invader following chemotactic gradients. Changes in microglial phenotype during activation may be analogous to that of peripheral macrophages, as the two cell types are indistinguishable without definitive surface markers for either. The M1 state(classical activation) consists of a phagocytic phenotype associated with transcriptional activation of NFk B, leading to production and release of proinflammatory cytokines and cytotoxic substances. The M2 state(alternative activation) also has a phagocyte phenotype but triggers anti-inflammatory responses via release of IL-10 and TGF-b or, alternatively, promotes tissue repair by releasing, for example, extracellular matrix proteins.Conclusion: The balance between the M1 and M2 states is dynamic in inflammatory responses and may be offset in cerebral ischemia, representing a novel mechanistic target for therapy.