Weng, Shih-YenWang, XiaoyuVijayan, SantoshTang, YilangKim, Yong OokPadberg, KorneliusRegen, TommyMolokanova, OlenaChen, TaoBopp, TobiasSchild, HansjörgBrombacher, FrankCrosby, Jeff R.McCaleb, Michael L.Waisman, AriBockamp, ErnestoSchuppan, Detlef2018-06-272018Weng, S., X. Wang, S. Vijayan, Y. Tang, Y. O. Kim, K. Padberg, T. Regen, et al. 2018. “IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal.” EBioMedicine 29 (1): 92-103. doi:10.1016/j.ebiom.2018.01.028. http://dx.doi.org/10.1016/j.ebiom.2018.01.028.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160270Chronic 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.en-USArg1, Arginase 1α-SMA, alpha–smooth muscle actinASO, antisense oligonucleotideBW, body weightCCL2, chemokine (C-C motif) ligand 2CClCol1a1, procollagen α1(I) transcriptDAPI, 4,6-diamidino-2-phenylindoleDKO, double knockoutECM, extracellular matrixGapdh, glyceraldehyde 3-phosphate dehydrogenaseHSC, hepatic stellate cellHyp, hydroxyprolineIFNγ, interferon-gammaIL-4Rα, interleukin-4 receptor alphaiNOS, inducible nitric oxide synthaseMMP, matrix metalloproteinaseMRC1, mannose receptor C type 1 (CD206)PDGF, platelet-derived growth factor betaqPCR, quantitative polymerase chain reactionSEM, standard error of the meanSTAT3/STAT6, signal transducer and activator of transcription 3 or 6TGFβ1, transforming growth factor beta 1 transcriptTIMP, tissue inhibitor of metalloproteinase 1TNF-α, tumor necrosis factor alphaWT, wildtypeFibrosisIL-4 receptor alphaLiverMacrophageMMP12ProgressionReversalJournal Article2018-06-2710.1016/j.ebiom.2018.01.028