• Authors: Weng, S. Y., Wang, X., Vijayan, S., Tang, Y., Kim, Y. O., Padberg, K., Regen, T., Molokanova, O., Chen, T., Bopp, T., Schild, H., Brombacher, F., Crosby, J. R., McCaleb, M. L., Waisman, A., Bockamp, E., Schuppan, D.
  • Year: 2018
  • Journal: EBioMedicine 29 92-103
  • Applications: in vitro / DNA / jetPEI-Macrophage
  • Cell type: RAW 264.7
    Description: Mouse monocytes/macrophages
    Known as: RAW


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 alpha (IL-4Ralpha), 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-4Ralpha(-/-) as well as in macrophage-specific IL-4Ralpha(-/-) (IL-4Ralpha(DeltaLysM)) mice. However, with deletion of IL-4Ralpha(DeltaLysM) spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Ralpha-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-4Ralpha 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-4Ralpha promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Ralpha induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Ralpha expression and attenuate fibrosis progression.