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Kim, Yong Ook
Crosby, Jeff R.
McCaleb, Michael L.
|Title:||IL-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal|
|Online publication date:||2-Aug-2018|
|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.|
610 Medical sciences
|Institution:||Johannes Gutenberg-Universität Mainz|
|Department:||FB 04 Medizin|
|Information on rights of use:||https://creativecommons.org/licenses/by-nc-nd/4.0/|
|Pages or article number:||92|
|Appears in collections:||JGU-Publikationen|