Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages.
Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages.
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DOI：
10.1186/1742-2094-9-246
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发表时间：
2012-10-30
影响因子：
9.3
通讯作者：
King NJ
中科院分区：
文献类型：
--
作者：
Getts DR;Terry RL;Getts MT;Müller M;Rana S;Deffrasnes C;Ashhurst TM;Radford J;Hofer M;Thomas S;Campbell IL;King NJ
Ly 6Chi单核细胞从血液中浸润是病毒性脑炎的标志。在由西尼罗河病毒（WNV）（一种新兴的嗜神经黄病毒）引起的致死性脑炎小鼠中，在第一次体重减轻和白细胞流入时通过抗极晚期抗原（VLA）-4整联蛋白抗体阻断Ly 6Chi单核细胞进入脑的抑制导致高达60%的感染小鼠的长期存活，随后具有灭菌免疫。这种处理对病毒滴度没有影响，但似乎是由于抑制Ly 6Chi巨噬细胞迁移。虽然从感染的脑中分离的巨噬细胞诱导WNV特异性CD 4 + T细胞增殖，但T细胞并不直接导致病理学，但可能在病毒控制中很重要，因为抗体介导的T细胞耗竭不能再现抗VLA-4的治疗益处。相反，发现70%的浸润性炎症单核细胞衍生的巨噬细胞产生一氧化氮（NO）。此外，氨基胍介导的抑制诱导的NO合酶活性浸润巨噬细胞显着延长生存，表明NO参与免疫病理学。这些数据首次显示了在嗜神经性病毒性脑炎期间暂时靶向致病性NO产生巨噬细胞的治疗效果。
Infiltration of Ly6Chi monocytes from the blood is a hallmark of viral encephalitis. In mice with lethal encephalitis caused by West Nile virus (WNV), an emerging neurotropic flavivirus, inhibition of Ly6Chi monocyte trafficking into the brain by anti-very late antigen (VLA)-4 integrin antibody blockade at the time of first weight loss and leukocyte influx resulted in long-term survival of up to 60% of infected mice, with subsequent sterilizing immunity. This treatment had no effect on viral titers but appeared to be due to inhibition of Ly6Chi macrophage immigration. Although macrophages isolated from the infected brain induced WNV-specific CD4+ T-cell proliferation, T cells did not directly contribute to pathology, but are likely to be important in viral control, as antibody-mediated T-cell depletion could not reproduce the therapeutic benefit of anti-VLA-4. Instead, 70% of infiltrating inflammatory monocyte-derived macrophages were found to be making nitric oxide (NO). Furthermore, aminoguanidine-mediated inhibition of induced NO synthase activity in infiltrating macrophages significantly prolonged survival, indicating involvement of NO in the immunopathology. These data show for the first time the therapeutic effects of temporally targeting pathogenic NO-producing macrophages during neurotropic viral encephalitis.