Pathogenic and Protective Functions of TNF in Neuroinflammation Are Defined by Its Expression in T Lymphocytes and Myeloid Cells
Pathogenic and Protective Functions of TNF in Neuroinflammation Are Defined by Its Expression in T Lymphocytes and Myeloid Cells
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DOI：
10.4049/jimmunol.1100663
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发表时间：
2011-12-01
影响因子：
4.4
通讯作者：
Nedospasov, Sergei A.
中科院分区：
文献类型：
--
作者：
Kruglov, Andrey A.;Lampropoulou, Vicky;Nedospasov, Sergei A.
TNF在许多自身免疫性疾病中显示致病活性。然而，抗肿瘤坏死因子治疗在多发性硬化症患者失败的原因尚不清楚。我们使用一组基因靶向小鼠，允许细胞类型特异性消融TNF，以揭示该细胞因子在中枢神经系统自身免疫性疾病中的致病和保护作用。在实验性自身免疫性脑脊髓炎（EAE）中，T细胞和骨髓细胞被发现是TNF的关键细胞来源。髓系细胞产生的TNF通过调节中枢神经系统中趋化因子的表达，加速疾病的发生，推动炎症细胞向靶器官募集。T细胞产生的TNF通过调节炎性髓细胞向中枢神经系统的浸润，加重了EAE过程中对中枢神经系统的损伤。在次级淋巴器官中，髓细胞和T细胞表达的TNF协同作用，抑制apc产生IL-12p40和IL-6，从而抑制Th1和Th17型脑源性T细胞反应的发展。肿瘤坏死因子在EAE中的双重作用（淋巴器官的保护性作用和中枢神经系统的致病性作用）表明，在多发性硬化症患者中，全面阻断肿瘤坏死因子可能是无效的，因为淋巴组织中自身反应性T细胞的增强可能会淹没肿瘤坏死因子抑制中枢神经系统产生的有益作用。中华免疫学杂志，2011,18(7):563 -567。
TNF displays pathogenic activities in many autoimmune disorders. However, anti-TNF therapy in multiple sclerosis patients failed because of poorly understood reasons. We used a panel of gene-targeted mice that allowed cell-type specific ablation of TNF to uncover pathogenic and protective contributions of this cytokine during autoimmune disease of the CNS. T cells and myeloid cells were found to be critical cellular sources of TNF during experimental autoimmune encephalomyelitis (EAE). TNF produced by myeloid cells accelerated the onset of disease by regulation of chemokine expression in the CNS, driving the recruitment of inflammatory cells into the target organ. TNF produced by T cells exacerbated the damage to the CNS during EAE by regulating infiltration of inflammatory myeloid cells into the CNS. In secondary lymphoid organs, TNF expressed by myeloid cells and T cells acted in synergy to dampen IL-12p40 and IL-6 production by APCs, subsequently inhibiting the development of encephalitogenic T cell responses of Th1 and Th17 types. This dual role of TNF during EAE (protective in lymphoid organs and pathogenic in CNS) suggests that global TNF blockade might be inefficient in multiple sclerosis patients because augmented autoreactive T cell development in lymphoid tissues might overwhelm the beneficial effects resulting from TNF inhibition in the CNS. The Journal of Immunology, 2011, 187: 5660-5670.