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

Journal of Neuroinflammation

Nicholas JC King¹  Iain L Campbell¹  Shane Thomas²  Markus Hofer¹  Jane Radford¹  Thomas Myles Ashhurst¹  Celine Deffrasnes¹  Sabita Rana¹  Marcus Müller¹  Meghann Teague Getts¹  Rachael L Terry¹  Daniel R Getts¹ 

[1] The Bosch Institute, University of Sydney, Sydney, Australia;The Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, Australia

关键词: Nitric oxide;    Integrins;    VLA-4;    Macrophage infiltration;    West Nile virus encephalitis;    Inflammatory monocytes;    Flavivirus;    Neurotropic virus;   

Others  :  1160171
DOI  :  10.1186/1742-2094-9-246

 received in 2012-06-12, accepted in 2012-09-28,  发布年份 2012

【 摘 要 】

Infiltration of Ly6C^hi 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 Ly6C^hi 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 Ly6C^hi 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.

【 授权许可】

   
2012 Getts et al.; licensee BioMed Central Ltd.

【 图 表 】

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