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

Abstract

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.

Regulation of inflammation in Japanese encephalitis

“…Upon JEV infection, various immune cell types increase in number in various compartments of the periphery, including the spleen, lymph nodes and blood. In mice, numbers of macrophages, inflammatory monocytes, granulocytes and pDC increase in lymphoid tissues, such as spleen and lymph nodes [ 19 , 29 , 36 ]. Although not dramatically, natural killer cell population decreased in the spleen of JEV-infected mice [ 19 ].…”

“…In mice, numbers of macrophages, inflammatory monocytes, granulocytes and pDC increase in lymphoid tissues, such as spleen and lymph nodes [ 19 , 29 , 36 ]. Although not dramatically, natural killer cell population decreased in the spleen of JEV-infected mice [ 19 ]. In the blood, leucocytosis characterized by high numbers of monocytes and neutrophils was found in human patients [ 50 , 61 ].…”

“…In the blood, leucocytosis characterized by high numbers of monocytes and neutrophils was found in human patients [ 50 , 61 ]. Similarly, JEV-infected mice show an increase of monocytes and neutrophils in blood [ 17 , 19 ].…”

“…Also, perivascular infiltrates and multifocal lymphohistiocytic meningitis are a hallmark of JEV-infected pigs [ 59 ] and macaques [ 44 ]. In mice, macrophages/monocytes are the majority of brain-infiltrating inflammatory myeloid cells [ 19 , 24 , 49 , 64 , 65 ]. In addition, granulocytes and NK cells also infiltrate the brain of JEV-infected mice [ 19 , 65 , 66 ].…”

“…JEV-induced inflammation contributes to disease severity by inducing neuronal cell death [ 13 , 14 ], inhibiting the proliferation and differentiation of neural progenitors [ 15 ] and disrupting the blood-brain barrier (BBB) [ 16 , 17 ]. Importantly, JEV-induced inflammation further modulates cytokine/chemokine production [ 18 ] as well as the activation and migration of cells [ 13 , 19 ]. Therefore, production of soluble factors and trafficking of immune cells may lead towards either disease progression or recovery through promotion of protective immune responses.…”