{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:09:52Z","timestamp":1792613392856,"version":"4.5.0"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T00:00:00Z","timestamp":1718064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","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>Background<\/jats:title>\n                    <jats:p>Inflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several chronic inflammatory diseases. However, increased liver fibrosis has been reported in mice lacking IL-15 receptor alpha chain (IL-15R\u03b1), suggesting an anti-fibrogenic role for IL-15. As myeloid cells are key players in liver fibrosis and IL-15 signaling can occur independently of IL-15R\u03b1, we investigated the requirement of IL-15 and IL-15R\u03b1 in liver fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We induced liver fibrosis in\n                      <jats:italic>\n                        Il15\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      ,\n                      <jats:italic>\n                        Il15ra\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      and wildtype C57BL\/6 mice by the administration of carbon tetrachloride (CCl\n                      <jats:sub>4<\/jats:sub>\n                      ). Liver fibrosis was evaluated by Sirius red and Mason\u2019s trichrome staining and \u03b1-smooth muscle acting immunostaining of myofibroblasts. Gene expression of collagens, matrix modifying enzymes, cytokines and chemokines was quantified by RT-qPCR. The phenotype and the numbers of intrahepatic lymphoid and myeloid cell subsets were evaluated by flow cytometry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both\n                      <jats:italic>\n                        Il15\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      and\n                      <jats:italic>\n                        Il15ra\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content.\n                      <jats:italic>\n                        Il15ra\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      mice showed further reduction in collagen deposition compared to\n                      <jats:italic>\n                        Il15\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      mice. However,\n                      <jats:italic>Col1a1<\/jats:italic>\n                      and\n                      <jats:italic>Col1a3<\/jats:italic>\n                      genes were similarly induced in the fibrotic livers of wildtype,\n                      <jats:italic>\n                        Il15\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      and\n                      <jats:italic>\n                        Il15ra\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected,\n                      <jats:italic>\n                        Il15\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      and\n                      <jats:italic>\n                        Il15ra\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45\n                      <jats:sup>+<\/jats:sup>\n                      immune cells and CD68\n                      <jats:sup>+<\/jats:sup>\n                      macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and anti-inflammatory monocyte subsets compared to wildtype mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings indicate that IL-15 exerts its profibrogenic role in the liver by promoting macrophage activation and that this requires trans-presentation of IL-15 by IL-15R\u03b1.<\/jats:p>\n                  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