CD40 express on by miroglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation
CD40 express on by miroglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation
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DOI：
10.4049/jimmunol.176.3.1402
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发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Dittel, BN
中科院分区：
文献类型：
--
作者：
Ponomarev, EA;Shriver, LP;Dittel, BN
小胶质细胞是一种单核细胞系细胞，存在于中枢神经系统，具有在各种病理条件下被激活的能力。尽管CD40-CD40L相互作用结合促炎细胞因子可在体外实现小胶质细胞的激活，但在中枢神经系统自身免疫过程中，体内介导小胶质细胞激活的确切因素尚不清楚。为了研究CD40在实验性自身免疫性脑脊髓炎(EAE)小胶质细胞激活中的作用，我们使用了骨髓嵌合体小鼠，使我们能够区分小胶质细胞和外周巨噬细胞，并使小胶质细胞缺乏CD40。我们发现小胶质细胞激活的第一步是不依赖于CD40的，并且发生在EAE发病期间。激活的第一步包括小胶质细胞的增殖和激活标志物MHC第二类、CD40和CD86的上调。在疾病的高峰期，小胶质细胞经历了第二阶段的激活，其特征是激活标志物的表达进一步增强，同时增殖减少。小胶质细胞活化的第二步是依赖CD40的，CD40缺陷的小胶质细胞在EAE期间未能达到完全激活水平，与脑源性T细胞在中枢神经系统的扩张和白细胞浸润减少以及临床症状的改善有关。因此，我们的研究结果表明，在EAE过程中，小胶质细胞上CD40的表达是完成其激活过程所必需的，这对疾病的进展是重要的。
Microglial cells are monocytic lineage cells that reside in the CNS and have the capacity to become activated during various pathological conditions. Although it was demonstrated that activation of microglial cells could be achieved in vitro by the engagement of CD40-CD40L interactions in combination with proinflammatory cytokines, the exact factors that mediate activation of microglial cells in vivo during CNS autoimmunity are ill-defined. To investigate the role of CD40 in microglial cell activation during experimental autoimmune encephalomyelitis (EAE), we used bone marrow chimera mice that allowed us to distinguish microglial cells from peripheral macrophages and render microglial cells deficient in CD40. We found that the first step of microglial cell activation was CD40-independent and occurred during EAE onset. The first step of activation consisted of microglial cell proliferation and up-regulation of the activation markers MHC class II, CD40, and CD86. At the peak of disease, microglial cells underwent a second step of activation, which was characterized by a further enhancement in activation marker expression along with a reduction in proliferation. The second step of microglial cell activation was CD40-dependent and the failure of CD40-deficient microglial cells to achieve a full level of activation during EAE was correlated with reduced expansion of encephalitogenic T cells and leukocyte infiltration in the CNS, and amelioration of clinical symptoms. Thus, our findings demonstrate that CD40 expression on microglial cells is necessary to complete their activation process during EAE, which is important for disease progression.