Authors:	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
Title:	IL-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal
Online publication date:	2-Aug-2018
Year of first publication:	2018
Language:	english
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:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	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
Publication type:	Zeitschriftenaufsatz
License:	CC BY-NC-ND
Information on rights of use:	https://creativecommons.org/licenses/by-nc-nd/4.0/
Journal:	EBioMedicine 29
Pages or article number:	92 103
Publisher:	Elsevier
Publisher place:	Amsterdam
Issue date:	2018
ISSN:	2352-3964
Publisher URL:	http://dx.doi.org/10.1016/j.ebiom.2018.01.028
Publisher DOI:	10.1016/j.ebiom.2018.01.028
Appears in collections:	JGU-Publikationen