2012年11月28日 訊 /生物谷BIOON/ --近日,，研究人員利用高分辨率的實(shí)時(shí)圖像在小鼠多發(fā)性硬化癥的早期階段揭示了神經(jīng)是如何損壞的,。研究結(jié)果表明,，關(guān)鍵步驟發(fā)生于當(dāng)血纖維蛋白原,、凝血蛋白滲漏進(jìn)入中樞神經(jīng)系統(tǒng)并激活小膠質(zhì)細(xì)胞時(shí),。研究論文發(fā)表在Nature Communications雜志上,。
多發(fā)性硬化癥或MS被認(rèn)為是一種自身免疫性疾病,，其中通常起保護(hù)身體免受感染的細(xì)胞攻擊大腦和脊髓中的神經(jīng)細(xì)胞,。通常在MS中,，免疫細(xì)胞破壞髓鞘，并最終導(dǎo)致神經(jīng)損傷,。
免疫系統(tǒng)攻擊導(dǎo)致血腦屏障滲漏,，博士Akassoglou一直專注于血腦屏障滲漏在MS中的作用，并發(fā)現(xiàn)滲漏的凝血蛋白纖維蛋白原可以觸發(fā)大腦炎癥,。
以往的研究表明,，滲漏的纖維蛋白原激活小膠質(zhì)細(xì)胞。在這項(xiàng)研究中,，Akassoglou博士和她的同事使用了最先進(jìn)的成像技術(shù)雙光子激光掃描顯微鏡研究MS動(dòng)物模型,。博士說(shuō)：我們的研究結(jié)果首次提供證據(jù)證實(shí)滲漏的纖維蛋白原與神經(jīng)元損傷有關(guān)。使用MS小鼠模型,，研究人員發(fā)現(xiàn)發(fā)生滲漏的纖維蛋白原和小膠質(zhì)細(xì)胞活化發(fā)生于神經(jīng)損傷開(kāi)始前,，它們發(fā)生在疾病的早期。
在此期間，小膠質(zhì)細(xì)胞改變形狀,，并與其他免疫細(xì)胞一起在血管周圍聚集,。進(jìn)一步的實(shí)驗(yàn)表明通過(guò)纖維蛋白原活化的小膠質(zhì)細(xì)胞結(jié)合受體CD11b/CD18，導(dǎo)致了小膠質(zhì)細(xì)胞釋放活性氧分子損傷神經(jīng)元,。因此抑制纖維蛋白原結(jié)合到受體能阻止小膠質(zhì)細(xì)胞的激活和神經(jīng)損傷,。目前治療MS的方法是抑制自身免疫。本研究的結(jié)果表明針對(duì)纖維蛋白原和小膠質(zhì)細(xì)胞之間的相互作用可能是一種有效的替代療法,。在小鼠中,，阻止纖維蛋白原的凝血活性能阻止小膠質(zhì)細(xì)胞的激活和神經(jīng)損傷。（生物谷：Bioon.com）
doi:10.1038/ncomms2230
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Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation
Davalos et al
Blood-brain barrier disruption, microglial activation and neurodegeneration are hallmarks of multiple sclerosis. However, the initial triggers that activate innate immune responses and their role in axonal damage remain unknown. Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation. Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo. Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia. Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage. Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease.
