Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation.
Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation.
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DOI：
10.1186/1742-2094-9-245
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发表时间：
2012-10-26
影响因子：
9.3
通讯作者：
Jain P
中科院分区：
文献类型：
--
作者：
Sagar D;Lamontagne A;Foss CA;Khan ZK;Pomper MG;Jain P
到目前为止，循环中的树突状细胞(DC)跨血脑屏障(BBB)进入中枢神经系统(CNS)的研究尚未见报道。趋化因子影响免疫细胞在血脑屏障的渗透、不受控制的激活和抗原提呈。趋化因子配体2(CCL2)是已知由血脑屏障分泌的一种强有力的趋化物质，但尚未参与树突状细胞在血脑屏障的募集。用MOG35-55多肽和百日咳毒素腹腔注射诱导C57BL/6小鼠实验性自身免疫性脑脊髓炎(EAE)。随着EAE评分的增加，动物被处死并接受近红外和荧光成像分析，以检测和定位CD11c+标记的DC相对于CCL2的表达。为了进一步研究CCL2在DC在血脑屏障转运中的直接作用，我们利用由人脑微血管内皮细胞组成的体外血脑屏障模型，比较了单核细胞来源的树突状细胞、CD4+和CD8+T细胞的迁移模式。此外，该模型被用来使用荧光显微镜对轮回进行成像，并评估涉及轮回的特定分子信号通路。DC移位的近红外成像与EAE期间炎症的严重程度相关。体外组织学证实在EAE病变中存在CCL2，树突状细胞从血管周围间隙中长出。在BBB模型研究中，DC比T细胞表现出更高的迁移效率。这些观察结果与跨孔成像相关，表明DC和T细胞的迁移是细胞旁的，而不是跨细胞的。此外，在分子水平上，CCL2似乎以ERK1/2依赖的方式促进DC的迁移。中枢神经系统树突状细胞的募集通过CCL2的趋化和跨血脑屏障的细胞旁迁移与EAE的疾病严重程度相关，ERK的激活促进了这一过程。总体而言，这些综合研究提供了对中枢神经系统内DC的最新看法，阐明了它们跨越血脑屏障的路径，并突出了CCL2介导的DC贩运的潜在机制。
Transmigration of circulating dendritic cells (DCs) into the central nervous system (CNS) across the blood–brain barrier (BBB) has not thus far been investigated. An increase in immune cell infiltration across the BBB, uncontrolled activation and antigen presentation are influenced by chemokines. Chemokine ligand 2 (CCL2) is a potent chemoattractant known to be secreted by the BBB but has not been implicated in the recruitment of DCs specifically at the BBB. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by injection of MOG35–55 peptide and pertussis toxin intraperitoneally. Animals with increasing degree of EAE score were sacrificed and subjected to near-infrared and fluorescence imaging analysis to detect and localize the accumulation of CD11c+-labeled DCs with respect to CCL2 expression. To further characterize the direct effect of CCL2 in DC trafficking at the BBB, we utilized an in vitro BBB model consisting of human brain microvascular endothelial cells to compare migratory patterns of monocyte-derived dendritic cells, CD4+ and CD8+ T cells. Further, this model was used to image transmigration using fluorescence microcopy and to assess specific molecular signaling pathways involved in transmigration. Near-infrared imaging of DC transmigration correlated with the severity of inflammation during EAE. Ex vivo histology confirmed the presence of CCL2 in EAE lesions, with DCs emerging from perivascular spaces. DCs exhibited more efficient transmigration than T cells in BBB model studies. These observations correlated with transwell imaging, which indicated a paracellular versus transcellular pattern of migration by DCs and T cells. Moreover, at the molecular level, CCL2 seems to facilitate DC transmigration in an ERK1/2-dependent manner. CNS recruitment of DCs correlates with disease severity in EAE via CCL2 chemotaxis and paracellular transmigration across the BBB, which is facilitated by ERK activation. Overall, these comprehensive studies provide a state-of-the-art view of DCs within the CNS, elucidate their path across the BBB, and highlight potential mechanisms involved in CCL2-mediated DC trafficking.
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影响因子：
3.3
作者：
Brini, E.;Ruffini, F.;Martino, G.
通讯作者：
Martino, G.
影响因子：
9.3
作者：
Chui R;Dorovini-Zis K
通讯作者：
Dorovini-Zis K
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
影响因子：
5.8
作者：
Cavone, Leonardo;Aldinucci, Alessandra;Chiarugi, Alberto
通讯作者：
Chiarugi, Alberto
影响因子：
9.3
作者：
Hinojosa AE;Garcia-Bueno B;Leza JC;Madrigal JL
通讯作者：
Madrigal JL