Deficiency of IL-20 receptor subunit A decreases enterovirus A71 lethality of mice with enhanced M1 macrophage polarization and cytokine

crossref(2024)

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Abstract Enterovirus A71 (EV-A71) can cause fatality in patients with increases of cytokines, IL-10, IL-12, and IFN-γ, which are mutually regulated. IFN-γ is induced and protects the host from EV-A71 in a murine infection model. IFN-γ and IL-10 promote the polarization of M1 and M2 macrophages, which produce IL-12 and IL-10, respectively. IL-10 suppresses IL-12, which enhances itself and IFN-γ. The IL-10 family cytokines, IL-19, IL-20, and IL-24, which signal through the two-subunit receptor complex with IL-20RA as one subunit, are therefore designated as IL-20RA cytokines. Previous in vitro T cell studies showed that IL-19 or IL-20 treatment suppresses IFN-γ and that IL-19 treatment enhances IL-10. In the present study of human plasma, IL-19 was detected in healthy controls, and EV-A71 infection increased IL-19 in patients. In the serum of mice, IL-20RA cytokines, but not IL-10, IL-12, and IFN-γ, were detected in mock-infected mice, and EV-A71 infection enhanced IL-19. Compared to wild-type mice, IL-20RA knockout mice were resistant to infection with reduced viral loads in peripheral organs, including the spleen. In infected mice, IL-20RA deficiency sequentially reduced IL-10, but increased IL-12 and IFN-γ, in the serum with T cells expressing IL-10 and macrophages expressing IL-12 and IFN-γ in the spleen. Notably, IL-20RA deficiency increased spleen M1 macrophages. In vitro study showed that treatment with IL-19 or IL-20, but not IL-24, increased IL-10 in CD4 T cells, but reduced IL-12 in macrophages. Our study is novel to show that IL-20RA cytokines affect virus infection, cytokines regulating macrophage polarization, and macrophage polarization.
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