Deficiency of IL-20 receptor subunit A decreases enterovirus A71 lethality in mice by increasing M1 macrophage polarization and cytokine production.

Introduction: Enterovirus A71 (EV-A71) can cause fatal disease accompanied by increased cytokines, including IL-10, IL-12, and IFN-γ, which are mutually regulated. IFN-γ is induced to protect mice from EV-A71 infection, but its regulation remains unclear. The IL-10 family cytokines, IL-19, IL-20, and IL-24, which signal through a two-subunit receptor complex containing IL-20 receptor subunit A (IL-20RA), are designated as IL-20RA cytokines. IL-20RA cytokines are known to regulate IFN-γ and IL-10 Methods: Plasma from healthy donors and EV-A71-infected patients was analyzed to detect IL-20RA cytokines. Wild-type (WT) and Results: In plasma samples, IL-19 was detectable in healthy controls, and EV-A71 infection increased IL-19 levels in infected patients. In sera of WT mice, IL-20RA cytokines, but not IL-10, IL-12, or IFN-γ, were detected in mock-infected animals, and EV-A71 infection significantly increased IL-19 and slightly increased IL-20 levels. Compared with WT mice, Discussion: EV-A71 infection enhances IL-20RA cytokines, which then increase viral loads and aggravate disease severity in WT mice by elevating the T cell-IL-10-M2 macrophage axis and suppressing the protective M1 macrophage-IL-12-macrophage-IFN-γ axis. This represents a previously unreported mechanism.