Rice RA,Pham J,Lee RJ,NajafiAR,West BL,Green KN

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Microglial repopulation resolves inflammation and promotes brain recovery after injury

Rice RA1,Pham J1,Lee RJ1,NajafiAR1,West BL2,Green KN1

1.Department of Neurobiology and Behavior,Institute for Memory Impairments and Neurological Disorders, University of California,Irvine,California,92697.

2.Plexxikon Inc,Berkeley,California,94710.

Microglia mediate chronic neuroinflammation following central nervous system(CNS)disease or injury,and in doing so,damage the local brain environment by impairing recovery and contributing to disease processes.Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor(CSF1R)and can be eliminated via administration of CSF1R inhibitors.Resolving chronic neuroinflammation represents a universal goal for CNS disorders,but long-term microglial elimination may not be amenable to clinical use.Notably, withdrawal of CSF1R inhibitors stimulates new microglia to fully repopulate the CNS,affording an opportunity to renew this cellular compartment.To that end,we have explored the effects of acute microglial elimination,followed by microglial repopulation,in a mouse model of extensive neuronal loss.Neuronal loss leads to a prolonged neuroinflammatory response,characterized by the presence of swollen microglia expressing CD68 and CD45,as well as elevated levels of cytokines,chemokines,complement,and other inflammatory signals.These collective responses are largely resolved by microglial repopulation.Furthermore,microglial repopulation promotes functional recovery in mice,with elevated plus maze performance matching that of uninjured mice,despite the loss of 80%of hippocampal neurons.Analyses of synaptic surrogates revealed increases in PSD95 and synaptophysin puncta with microglial repopulation,suggesting that these cells sculpt and regulate the synaptic landscape.Thus,our results show that short-term microglial elimination followed by repopulation may represent a clinically feasible and novel approach to resolve neuroinflammatory events and promote brain recovery.

colony-stimulating factor 1 receptor;dendritic spines;glia;neuroinflammation;neuronal loss

（編譯：唐穎馨）

摘 自《GLIA》2017, 65:931-944.

小膠質(zhì)細(xì)胞再激活可緩解腦損傷后炎癥反應(yīng)并促進(jìn)腦功能恢復(fù)

中樞神經(jīng)系統(tǒng)疾病或損傷后，小膠質(zhì)細(xì)胞介導(dǎo)的慢性神經(jīng)炎癥反應(yīng)會(huì)損傷局部腦組織，加重病情，不利于神經(jīng)功能的恢復(fù)。小膠質(zhì)細(xì)胞的激活通過集落刺激因子1受體（CSF1R）信號(hào)通路，CSF1R抑制劑可阻斷小膠質(zhì)細(xì)胞的激活。抑制慢性神經(jīng)炎癥反應(yīng)是治療中樞神經(jīng)系統(tǒng)疾病的有效方法，但長(zhǎng)時(shí)間抑制小膠質(zhì)細(xì)胞在臨床實(shí)踐中無法實(shí)現(xiàn)。值得注意的是，去掉CSF1R抑制劑可刺激中樞神經(jīng)系統(tǒng)內(nèi)新的小膠質(zhì)細(xì)胞的徹底重激活。本課題組建立小鼠廣泛性神經(jīng)元丟失模型，在該模型中探討急性小膠質(zhì)細(xì)胞的消除及再激活的作用。神經(jīng)元的丟失導(dǎo)致了較長(zhǎng)時(shí)間的神經(jīng)炎性反應(yīng)，表現(xiàn)為小膠質(zhì)細(xì)胞腫脹，并表達(dá)CD68和CD45；同時(shí)，細(xì)胞因子、趨化因子、補(bǔ)體及其他炎癥信號(hào)的表達(dá)增加。小膠質(zhì)細(xì)胞的再激活可以緩解上述炎癥反應(yīng)，還可以促進(jìn)小鼠神經(jīng)功能的恢復(fù)，即使該小鼠的海馬神經(jīng)元丟失80%，其在水迷宮測(cè)試中的得分與正常小鼠的得分相差無幾。對(duì)突觸的分析結(jié)果顯示，小膠質(zhì)細(xì)胞的再激活可增加PSD95和突觸泡蛋白點(diǎn)狀突觸體的表達(dá)，提示小膠質(zhì)細(xì)胞有助于重塑和調(diào)節(jié)突觸的形態(tài)和功能。綜上所述，本研究結(jié)果顯示，小膠質(zhì)細(xì)胞的短時(shí)間消除及再激活可能是一種新穎有效的方法用于減少神經(jīng)炎性反應(yīng)并促進(jìn)腦功能恢復(fù)。

集落刺激因子1受體；樹突棘；膠質(zhì)細(xì)胞；神經(jīng)炎癥反應(yīng)；神經(jīng)元丟失

R741

ADOI10.16780/j.cnki.sjssgncj.2017.01.035