IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal
Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239641830032X |
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doaj-9adbad462d3d45debb61ce2ce372aca5 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Shih-Yen Weng Xiaoyu Wang Santosh Vijayan Yilang Tang Yong Ook Kim Kornelius Padberg Tommy Regen Olena Molokanova Tao Chen Tobias Bopp Hansjörg Schild Frank Brombacher Jeff R. Crosby Michael L. McCaleb Ari Waisman Ernesto Bockamp Detlef Schuppan |
| spellingShingle |
Shih-Yen Weng Xiaoyu Wang Santosh Vijayan Yilang Tang Yong Ook Kim Kornelius Padberg Tommy Regen Olena Molokanova Tao Chen Tobias Bopp Hansjörg Schild Frank Brombacher Jeff R. Crosby Michael L. McCaleb Ari Waisman Ernesto Bockamp Detlef Schuppan IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal EBioMedicine |
| author_facet |
Shih-Yen Weng Xiaoyu Wang Santosh Vijayan Yilang Tang Yong Ook Kim Kornelius Padberg Tommy Regen Olena Molokanova Tao Chen Tobias Bopp Hansjörg Schild Frank Brombacher Jeff R. Crosby Michael L. McCaleb Ari Waisman Ernesto Bockamp Detlef Schuppan |
| author_sort |
Shih-Yen Weng |
| title |
IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal |
| title_short |
IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal |
| title_full |
IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal |
| title_fullStr |
IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal |
| title_full_unstemmed |
IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal |
| title_sort |
il-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal |
| publisher |
Elsevier |
| series |
EBioMedicine |
| issn |
2352-3964 |
| publishDate |
2018-03-01 |
| description |
Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα−/− as well as in macrophage-specific IL-4Rα−/− (IL-4RαΔLysM) mice. However, with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. Research in Context: Alternative (M2-type) macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression. Keywords: Fibrosis, IL-4 receptor alpha, Liver, Macrophage, MMP12, Progression, Reversal |
| url |
http://www.sciencedirect.com/science/article/pii/S235239641830032X |
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doaj-9adbad462d3d45debb61ce2ce372aca52020-11-25T00:59:38ZengElsevierEBioMedicine2352-39642018-03-012992103IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and ReversalShih-Yen Weng0Xiaoyu Wang1Santosh Vijayan2Yilang Tang3Yong Ook Kim4Kornelius Padberg5Tommy Regen6Olena Molokanova7Tao Chen8Tobias Bopp9Hansjörg Schild10Frank Brombacher11Jeff R. Crosby12Michael L. McCaleb13Ari Waisman14Ernesto Bockamp15Detlef Schuppan16Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, GermanyInstitute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, GermanyInstitute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University, Mainz, GermanyInstitute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, GermanyInstitute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University, Mainz, GermanyInstitute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, GermanyInstitute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute for Immunology, University Medical Center, Johannes Gutenberg University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute for Immunology, University Medical Center, Johannes Gutenberg University, Mainz, GermanyInternational Center for Genetic Engineering and Biotechnology, Institute of Infectious Disease and Molecular Medicine, South African Medical Research Council, Cape Town, South AfricaIonis Pharmaceuticals, Carlsbad, CA, United StatesIonis Pharmaceuticals, Carlsbad, CA, United StatesResearch Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University, Mainz, GermanyInstitute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, GermanyInstitute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Corresponding author at: Institute of Translational Immunology, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα−/− as well as in macrophage-specific IL-4Rα−/− (IL-4RαΔLysM) mice. However, with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. Research in Context: Alternative (M2-type) macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression. Keywords: Fibrosis, IL-4 receptor alpha, Liver, Macrophage, MMP12, Progression, Reversalhttp://www.sciencedirect.com/science/article/pii/S235239641830032X |