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

Kim, Jin Hyoung; Patil, Ajit Mahadev; Choi, Jin Young; Kim, Seong Bum; Uyangaa, Erdenebileg; Hossain, Ferdaus Mohd Altaf; Park, Sang‐Youel; Lee, John Hwa; Kim, Koanhoi; Eo, Seong Kug

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.