Herpes simplex virus (HSV)-1 encephalitis has significant morbidity partly because of an over-exuberant immune response characterized by leukocyte infiltration into the brain and increased blood-brain barrier (BBB) permeability. Determining the role of specific leukocyte subsets and the factors that mediate their recruitment into the brain is critical to developing targeted immune therapies. In a murine model, we find that the chemokines CXCL1 and CCL2 are induced in the brain following HSV-1 infection. Ccr2 (CCL2 receptor)-deficient mice have reduced monocyte recruitment, uncontrolled viral replication, and increased morbidity. Contrastingly, Cxcr2 (CXCL1 receptor)-deficient mice exhibit markedly reduced neutrophil recruitment, BBB permeability, and morbidity, without influencing viral load. CXCL1 is produced by astrocytes in response to HSV-1 and by astrocytes and neurons in response to IL-1α, and it is the critical ligand required for neutrophil transendothelial migration, which correlates with BBB breakdown. Thus, the CXCL1-CXCR2 axis represents an attractive therapeutic target to limit neutrophil-mediated morbidity in HSV-1 encephalitis.

单纯疱疹病毒 (HSV)-1 脑炎的发病率很高，部分原因是免疫反应过度旺盛，其特征是白细胞浸润到大脑和血脑屏障 (BBB) 通透性增加。确定特定白细胞亚群的作用以及介导它们向大脑募集的因素对于开发靶向免疫疗法至关重要。在鼠模型中，我们发现趋化因子 CXCL1 和 CCL2 在 HSV-1 感染后在大脑中被诱导。Ccr2（CCL2 受体）缺陷小鼠的单核细胞募集减少、病毒复制失控和发病率增加。相比之下，Cxcr2（CXCL1 受体）缺陷小鼠表现出显着降低的中性粒细胞募集、BBB 通透性和发病率，而不会影响病毒载量。CXCL1 由星形胶质细胞响应 HSV-1 以及星形胶质细胞和神经元响应 IL-1α 产生，它是中性粒细胞跨内皮迁移所需的关键配体，与 BBB 分解相关。因此，CXCL1-CXCR2 轴代表了一个有吸引力的治疗靶点，可以限制 HSV-1 脑炎中中性粒细胞介导的发病率。