CCL2, but not its receptor, is essential to restrict immune privileged central nervous system-invasion of Japanese encephalitis virus via regulating accumulation of CD11b(+) Ly-6C(hi) monocytes.
Japanese encephalitis virus (JEV) is a re-emerging zoonotic flavivirus that poses an increasing threat to global health and welfare due to rapid changes in climate and demography. Although the CCR2-CCL2 axis plays an important role in trafficking CD11b(+) Ly-6C(hi) monocytes to regulate immunopathological diseases, little is known about their role in monocyte trafficking during viral encephalitis caused by JEV infection. Here, we explored the role of CCR2 and its ligand CCL2 in JE caused by JEV infection using CCR2- and CCL2-ablated murine models. Somewhat surprisingly, the ablation of CCR2 and CCL2 resulted in starkly contrasting susceptibility to JE. CCR2 ablation induced enhanced resistance to JE, whereas CCL2 ablation highly increased susceptibility to JE. This contrasting regulation of JE progression by CCR2 and CCL2 was coupled to central nervous system (CNS) infiltration of Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. There was also enhanced expression of CC and CXC chemokines in the CNS of CCL2-ablated mice, which appeared to induce CNS infiltration of these cell populations. However, our data revealed that contrasting regulation of JE in CCR2- and CCL2-ablated mice was unlikely to be mediated by innate natural killer and adaptive T-cell responses. Furthermore, CCL2 produced by haematopoietic stem cell-derived leucocytes played a dominant role in CNS accumulation of Ly-6C(hi) monocytes in infected bone marrow chimeric models, thereby exacerbating JE progression. Collectively, our data indicate that CCL2 plays an essential role in conferring protection against JE caused by JEV infection. In addition, blockage of CCR2, but not CCL2, will aid in the development of strategies for prophylactics and therapeutics of JE.
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.
Jin Hyoung
JH
Kim
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.
Ajit Mahadev
AM
Patil
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.
Jin Young
JY
Choi
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.
Seong Bum
SB
Kim
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.
Erdenebileg
E
Uyangaa
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.
Ferdaus Mohd Altaf
FM
Hossain
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.|Department of Bioactive Material Sciences, Graduate School, Chonbuk National University, Jeonju, Korea.
Sang-Youel
SY
Park
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.|Department of Bioactive Material Sciences, Graduate School, Chonbuk National University, Jeonju, Korea.
John Hwa
JH
Lee
Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Korea.
Koanhoi
K
Kim
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Korea.|Department of Bioactive Material Sciences, Graduate School, Chonbuk National University, Jeonju, Korea.
Seong Kug
SK
Eo
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000502:physiology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004664:Encephalitis Virus, Japanese / Q000276:immunology*; D004672:Encephalitis, Japanese / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*
D000950:Antigens, Ly; D039481:CD11b Antigen; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2
CCL2; CCR2; Japanese encephalitis; Ly-6Chi monocytes; neuroinflammation