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Autoren: Weng, Shih-Yen
Wang, Xiaoyu
Vijayan, Santosh
Tang, Yilang
Kim, Yong Ook
Padberg, Kornelius
Regen, Tommy
Molokanova, Olena
Chen, Tao
Bopp, Tobias
Schild, Hansjörg
Brombacher, Frank
Crosby, Jeff R.
McCaleb, Michael L.
Waisman, Ari
Bockamp, Ernesto
Schuppan, Detlef
Titel: IL-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal
Online-Publikationsdatum: 2-Aug-2018
Erscheinungsdatum: 2018
Sprache des Dokuments: Englisch
Zusammenfassung/Abstract: Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause ofworldwide 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−/− aswell 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.
DDC-Sachgruppe: 610 Medizin
610 Medical sciences
Veröffentlichende Institution: Johannes Gutenberg-Universität Mainz
Organisationseinheit: FB 04 Medizin
Veröffentlichungsort: Mainz
ROR: https://ror.org/023b0x485
DOI: http://doi.org/10.25358/openscience-799
URN: urn:nbn:de:hebis:77-publ-584084
Version: Published version
Publikationstyp: Zeitschriftenaufsatz
Nutzungsrechte: CC BY-NC-ND
Informationen zu den Nutzungsrechten: https://creativecommons.org/licenses/by-nc-nd/4.0/
Zeitschrift: EBioMedicine
29
Seitenzahl oder Artikelnummer: 92
103
Verlag: Elsevier
Verlagsort: Amsterdam
Erscheinungsdatum: 2018
ISSN: 2352-3964
URL der Originalveröffentlichung: http://dx.doi.org/10.1016/j.ebiom.2018.01.028
DOI der Originalveröffentlichung: 10.1016/j.ebiom.2018.01.028
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