Cell Journal: Small glial cell recolonization plays a neuroprotective role in brain injury.

The pathological mechanism of traumatic brain injury (TBI) is complex and multifactorial. According to the pathological changes of brain injury, brain injury is usually divided into primary and secondary injury.secondary injury triggered by craniocerebral trauma mainly includes excitotoxicity, local ischemia, apoptosis, necrosis and inflammation, which are caused by a series of neurobiochemical processes, resulting in neurological dysfunction.neuroinflammation is the main pathological process of secondary injury after TBI.microglia are the specific immune cells of the brain, which have the function of phagocytosis and antigen presentation.in normal physiological state, microglia "monitor" the microenvironment of the brain in a resting state, and immediately enter the injured site to play a role when brain injury occurs.autopsy samples of brain injury showed that the activation of microglia persisted, even after several years of injury.in the early stage of injury, microglia rapidly release inflammatory factors related to injury and migrate to the injured site, which is conducive to brain repair.however, the subsequent sustained activation of microglia is harmful.can we delete microglia during brain injury, and then let them "grow out" again, so as to avoid the continuous activation of microglia? In fact, this process is called microglia regrowth Green's team found that microglia in the brain could be almost completely knocked out by specifically inhibiting colony stimulating factor-1 receptor (csf1r) (> 99%); however, new microglia appeared in the brain after a short recovery period and the inhibition was stopped.these regenerated microglia can colonize the whole brain rapidly and return to their original state in about a week.this phenomenon has been widely questioned, mainly focusing on the origin of regrowth microglia.in 2018, Chinese scholar Peng Bo's team first found that all the re colonized microglia were derived from the residual primary microglia (< lt; 1%) in the central nervous system by means of rigorous multi lineage tracking technology through a variety of transgenic mice, and confirmed that the re colonized microglia originated from the residual microglia.it's true that the wild fire can't be burned out, and the spring wind blows again.in addition, microglia are involved in cognitive impairment, and there are also serious cognitive impairment in TBI, but whether microglia participate in cognitive impairment in TBI is still unknown.March 5, 2020, Jana Vukovic, a research team from the University of Queensland, Australia, published an article in the journal Cell, which revealed that microglia can alleviate cognitive impairment through IL-6 signaling pathway in brain injury.the researchers first adopted the scheme of continuous microglia knockout: before TBI Model (3 weeks ago) and after (2 weeks) continuous treatment with mouse colony stimulating factor-1 receptor inhibitor plx5622, and on the 12th day after TBI model establishment, the number of microglia in hippocampus of TBI model mice increased by 5 times as much as that of normal group The number of microglia in mice fed with plx5622 was small.through behavioral tests such as active position preference and water maze, it was further found that continuous microglia knockout did not improve the spatial learning and memory impairment caused by brain injury, nor could it alleviate the disturbance of hippocampal nerve regeneration caused by brain injury. therefore, long-term microglia knockout does not improve the cognitive impairment of TBI. using the characteristics of microglia regrowth, they changed the experimental scheme to make microglia disappear first and then appear: CRE mice induced by tamoxifen effectively knocked out microglia and then made TBI Model, and then no tamoxifen was given. This means that microglia were no longer knocked out after TBI Model operation, and appeared on the second day after operation The number of microglia reached the level of sham operation group on the 3rd day, and reached the level of TBI mice on the 7th day. the same results were obtained by plx5622 pharmacological means. generally speaking, the rate of microglia regrowth is still very fast. At the same time, we should pay attention to the fact that the branches of microglia are more and longer on the third day after operation, which is not explained in the article. The author thinks that this may be caused by the inflammatory environment formed after brain injury. surprisingly, multiple behavioral studies such as active position preference and water maze found that microglia regrowth after brain injury can improve spatial learning and memory ability and promote hippocampal nerve regeneration. although this promoting effect can not restore cognitive ability and hippocampal nerve regeneration to normal level, it does play a beneficial role in promoting. Moreover, the evidence chain of causality in this paper is very obvious. Therefore, microglia can promote brain repair in the early stage of brain injury. the next step is to look for the molecular mechanism of neuroprotective effect of microglia regrowth. through the experiment of gene expression related to inflammatory molecules, they found that only the expression of IL-6 in hippocampus increased significantly in the early stage of brain injury, and further found that IL-6 was produced by hippocampal granulosa cells. In addition, the expression of IL-6 receptor A, IL6 signal transduction molecule (il6st / gp130) and other molecules related to IL6 signaling pathway were up-regulated. Therefore, they think that the IL-6 signaling pathway may be Microglia are important molecular targets for neuroprotection. this conclusion was verified in subsequent experiments, and the neuroprotective effect of microglia regrowth can be cancelled by blocking antibody with IL-6 receptor. on the selection of IL-6 as a target, the author has some own views: from the above figure, we can see that the expression of IL6 and ZEB genes is up-regulated during microglia regrowth. Statistically speaking, IL6 is more obvious and more likely. from the perspective of time dimension, ZEB is continuously increased during microglia regrowth. Is ZEB also a target of neuroprotective effect of microglia regrowth (to state, the author is not a prick, just put forward some views on this target). finally, through the current very, special, special, very popular single cell sequencing technology, the researchers found that the microglia formed during the re colonization had different characteristics: increased expression of molecules related to wound healing and decreased molecular expression related to interferon signaling pathway. in conclusion, we found that microglia regeneration in the early stage of brain injury is beneficial to brain repair through a variety of transgenic mice, and this neuroprotective effect is mediated by the IL6 signaling pathway. this provides a potential target for early treatment of brain injury. References: 1, Unmasking a Microglia Progenitor Cell in the Adult Brain2.Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion3.Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner