Lee Dhong Hyun, Ghiasi Homayon
Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns and Allen Research Institute, Los Angeles, California, USA.
Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns and Allen Research Institute, Los Angeles, California, USA
J Virol. 2017 Jul 12;91(15). doi: 10.1128/JVI.00578-17. Print 2017 Aug 1.
Macrophages are the predominant infiltrate in the corneas of mice that have been ocularly infected with herpes simplex virus 1 (HSV-1). However, very little is known about the relative roles of M1 (classically activated or polarized) and M2 (alternatively activated or polarized) macrophages in ocular HSV-1 infection. To better understand these relationships, we assessed the impact of directed M1 or M2 activation of RAW264.7 macrophages and peritoneal macrophages (PM) on subsequent HSV-1 infection. In both the RAW264.7 macrophage and PM models, HSV-1 replication in M1 macrophages was markedly lower than in M2 macrophages and unstimulated controls. The M1 macrophages expressed significantly higher levels of 28 of the 32 tested cytokines and chemokines than M2 macrophages, with HSV-1 infection significantly increasing the levels of proinflammatory cytokines and chemokines in the M1 versus the M2 macrophages. To examine the effects of shifting the immune response toward either M1 or M2 macrophages , wild-type mice were injected with gamma interferon (IFN-γ) DNA or colony-stimulating factor 1 (CSF-1) DNA prior to ocular infection with HSV-1. Virus replication in the eye, latency in trigeminal ganglia (TG), and markers of T cell exhaustion in the TG were determined. We found that injection of mice with IFN-γ DNA, which enhances the development of M1 macrophages, increased virus replication in the eye; increased latency; and also increased CD4, CD8, IFN-γ, and PD-1 transcripts in the TG of latently infected mice. Conversely, injection of mice with CSF-1 DNA, which enhances the development of M2 macrophages, was associated with reduced virus replication in the eye and reduced latency and reduced the levels of CD4, CD8, IFN-γ,and PD-1 transcripts in the TG. Collectively, these results suggest that M2 macrophages directly reduce the levels of HSV-1 latency and, thus, T-cell exhaustion in the TG of ocularly infected mice. Our findings demonstrate a novel approach to further reducing HSV-1 replication in the eye and latency in the TG by modulating immune components, specifically, by altering the phenotype of macrophages. We suggest that inclusion of CSF-1 as part of any vaccination regimen against HSV infection to coax responses of macrophages toward an M2, rather than an M1, response may further improve vaccine efficacy against ocular HSV-1 replication and latency.
巨噬细胞是眼部感染单纯疱疹病毒1型（HSV-1）的小鼠角膜中的主要浸润细胞。然而，关于M1（经典激活或极化）和M2（交替激活或极化）巨噬细胞在眼部HSV-1感染中的相对作用，我们知之甚少。为了更好地理解这些关系，我们评估了RAW264.7巨噬细胞和腹腔巨噬细胞（PM）的定向M1或M2激活对随后HSV-1感染的影响。在RAW264.7巨噬细胞和PM模型中，HSV-1在M1巨噬细胞中的复制明显低于M2巨噬细胞和未刺激的对照。与M2巨噬细胞相比，M1巨噬细胞表达的32种测试细胞因子和趋化因子中有28种水平显著更高，HSV-1感染显著增加了M1巨噬细胞中促炎细胞因子和趋化因子的水平，而M2巨噬细胞中则不然。为了研究将免疫反应转向M1或M2巨噬细胞的影响，在用HSV-1眼部感染之前，给野生型小鼠注射γ干扰素（IFN-γ）DNA或集落刺激因子1（CSF-1）DNA。测定了眼睛中的病毒复制、三叉神经节（TG）中的潜伏情况以及TG中T细胞耗竭的标志物。我们发现，给小鼠注射IFN-γ DNA可增强M1巨噬细胞的发育，增加眼睛中的病毒复制；增加潜伏时间；还增加了潜伏感染小鼠TG中的CD4、CD8、IFN-γ和PD-1转录本。相反，给小鼠注射CSF-1 DNA可增强M2巨噬细胞的发育，这与眼睛中病毒复制减少、潜伏时间缩短以及TG中CD4、CD8、IFN-γ和PD-1转录本水平降低有关。总体而言，这些结果表明，M2巨噬细胞可直接降低眼部感染小鼠TG中HSV-1的潜伏水平，从而降低T细胞耗竭程度。我们的研究结果表明了一种新方法，即通过调节免疫成分，特别是通过改变巨噬细胞的表型，进一步降低眼睛中HSV-1的复制和TG中的潜伏情况。我们建议，在任何针对HSV感染的疫苗接种方案中加入CSF-1，以促使巨噬细胞产生M2而非M1反应，这可能会进一步提高疫苗对眼部HSV-1复制和潜伏的疗效。
