Polarization of Type 1 Macrophages Is Associated with the Severity of Viral Encephalitis Caused by Japanese Encephalitis Virus and Dengue Virus

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 11; p. 3181
• Main Authors: Jhan, Ming-Kai, Chen, Chia-Ling, Shen, Ting-Jing, Tseng, Po-Chun, Wang, Yung-Ting, Satria, Rahmat Dani, Yu, Chia-Yi, Lin, Chiou-Feng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.11.2021; MDPI
• Subjects: Animal models; Animals; Animals, Suckling; Antibodies; Brain; Brain injury; Cell activation; Cell Line; Cell Polarity; Chemokine receptors; Dengue fever; dengue virus; Dengue Virus - physiology; Disease; Disease Models, Animal; Encephalitis; Encephalitis Virus, Japanese - physiology; Encephalitis, Japanese - immunology; Encephalitis, Japanese - pathology; Encephalitis, Japanese - virology; Encephalitis, Viral - immunology; Encephalitis, Viral - pathology; Encephalitis, Viral - virology; Flaviviridae; flavivirus; Genomes; Hemorrhage; Hemorrhagic fever; Hippocampus - pathology; Infections; Inflammation; Inflammation - pathology; Leukocytes (mononuclear); macrophage; Macrophages; Macrophages - pathology; Mice; Mice, Inbred ICR; Microglia; Mortality; Neurotoxicity; Neurotoxins - toxicity; Paralysis; Phenotypes; Polarization; Proteins; Reagents; Receptors, CCR2 - metabolism; Seizures; Severity of Illness Index; Stains & staining; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Viral infections; Viruses; West Nile virus; St Louis Missouri; United Kingdom > UK; United States > US; Taiwan; macrophage; polarization; encephalitis; dengue virus; flavivirus
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10113181

Infection with flaviviruses causes mild to severe diseases, including viral hemorrhagic fever, vascular shock syndrome, and viral encephalitis. Several animal models explore the pathogenesis of viral encephalitis, as shown by neuron destruction due to neurotoxicity after viral infection. While neuronal cells are injuries caused by inflammatory cytokine production following microglial/macrophage activation, the blockade of inflammatory cytokines can reduce neurotoxicity to improve the survival rate. This study investigated the involvement of macrophage phenotypes in facilitating CNS inflammation and neurotoxicity during flavivirus infection, including the Japanese encephalitis virus, dengue virus (DENV), and Zika virus. Mice infected with different flaviviruses presented encephalitis-like symptoms, including limbic seizure and paralysis. Histology indicated that brain lesions were identified in the hippocampus and surrounded by mononuclear cells. In those regions, both the infiltrated macrophages and resident microglia were significantly increased. RNA-seq analysis showed the gene profile shifting toward type 1 macrophage (M1) polarization, while M1 markers validated this phenomenon. Pharmacologically blocking C-C chemokine receptor 2 and tumor necrosis factor-α partly retarded DENV-induced M1 polarization. In summary, flavivirus infection, such as JEV and DENV, promoted type 1 macrophage polarization in the brain associated with encephalitic severity.