期刊
CELL REPORTS
卷 32, 期 11, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.108150
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资金
- National Institutes of Health [R01 NS098747]
- Wellcome Trust
- National Institute for Health Research
- Medical Research Council (MRC)
- Academy of Medical Sciences
- British Medical Association
- British Infection Association
- Medical Research Council-Japan Agency for Medical Research and Development (MRC-AMED) Infectious Disease Research Collaboration [MR/T028750/JPjm0210069h]
- National Institute for Health Research (NIHR) Health Protection Research Unit in Emerging and Zoonotic Infections [IS-HPU-1112-10117, NIHR200907]
- NIHR Global Health Research Group on Brain Infections [17/63/110]
- European Union's Horizon 2020 research and innovation program ZikaPLAN (Preparedness Latin America Network) [734584]
- MRC [MR/T028750/1] Funding Source: UKRI
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-1 alpha, 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.
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