Profibrogenic role of IL-15 through IL-15 receptor alpha-mediated trans-presentation in the carbon tetrachloride-induced liver fibrosis model

• Published in: Frontiers in immunology Vol. 15; p. 1404891
• Main Authors: Cloutier, Maryse, Variya, Bhavesh, Akbari, Sara Ali, Rexhepi, Fjolla, Ilangumaran, Subburaj, Ramanathan, Sheela
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2024
• Subjects: Animals; carbon tetra chloride (CCl) 4; Carbon Tetrachloride; Cytokines - metabolism; Disease Models, Animal; IL-15; IL-15Rα; Interleukin-15 - genetics; Interleukin-15 - metabolism; Interleukin-15 Receptor alpha Subunit - genetics; Interleukin-15 Receptor alpha Subunit - metabolism; Liver - immunology; Liver - metabolism; Liver - pathology; Liver Cirrhosis - chemically induced; Liver Cirrhosis - immunology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; liver fibrosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; pre-clinical study; Receptors, Interleukin-15; IL-15; carbon tetra chloride (CCl) 4; liver fibrosis; pre-clinical study; IL-15Rα
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1404891

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-15Rα), 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-15Rα, we investigated the requirement of IL-15 and IL-15Rα in liver fibrosis. We induced liver fibrosis in , and wildtype C57BL/6 mice by the administration of carbon tetrachloride (CCl ). Liver fibrosis was evaluated by Sirius red and Mason's trichrome staining and α-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. Both and mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content. mice showed further reduction in collagen deposition compared to mice. However, and genes were similarly induced in the fibrotic livers of wildtype, and mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected, and mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45 immune cells and CD68 macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and anti-inflammatory monocyte subsets compared to wildtype mice. 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-15Rα.