{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T06:32:56Z","timestamp":1767335576385,"version":"3.48.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Enterovirus A71 (EV-A71) can cause fatal disease accompanied by increased cytokines, including IL-10, IL-12, and IFN-\u03b3, which are mutually regulated. IFN-\u03b3 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-\u03b3 and IL-10\n                      <jats:italic>in vitro<\/jats:italic>\n                      . We designed this study to investigate the interaction and role of IL-20RA cytokines in viral infection\n                      <jats:italic>in vivo<\/jats:italic>\n                      , which remain unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Plasma from healthy donors and EV-A71-infected patients was analyzed to detect IL-20RA cytokines. Wild-type (WT) and\n                      <jats:italic>IL-20RA<\/jats:italic>\n                      knockout (\n                      <jats:italic>IL-20RA<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      ) mice, as well as isolated T cells and macrophages, were used for functional studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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-\u03b3, were detected in mock-infected animals, and EV-A71 infection significantly increased IL-19 and slightly increased IL-20 levels. Compared with WT mice,\n                      <jats:italic>IL-20RA<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice were resistant to EV-A71 infection, with reduced viral loads in peripheral organs, such as the spleen. In sera of infected mice, IL-20RA deficiency sequentially reduced IL-10 levels but increased IL-12 and IFN-\u03b3 levels. Abundant T cells expressed IL-10 in splenocytes of infected WT mice, whereas abundant macrophages expressed IL-12 and IFN-\u03b3 in splenocytes of infected\n                      <jats:italic>IL-20RA<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. Notably, IL-20RA deficiency reduced M2 macrophages but increased M1 macrophages in splenocytes of infected mice.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , treatment of leukocytes isolated from WT mice with IL-19 or IL-20, but not IL-24, increased IL-10 production in CD4 T cells and reduced IL-12 production in macrophages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>EV-A71 infection enhances IL-20RA cytokines, which then increase viral loads and aggravate disease severity in WT mice by elevating the T cell\u2013IL-10\u2013M2 macrophage axis and suppressing the protective M1 macrophage\u2013IL-12\u2013macrophage\u2013IFN-\u03b3 axis. This represents a previously unreported mechanism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1700154","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T06:28:14Z","timestamp":1767335294000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Deficiency of IL-20 receptor subunit A decreases enterovirus A71 lethality in mice by increasing M1 macrophage polarization and cytokine 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