Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
EBioMedicine. 2018 Mar;29:92-103. doi: 10.1016/j.ebiom.2018.01.028. Epub 2018 Feb 17.
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 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-4Rα) mice. However, with deletion of IL-4Rα 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.
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.
慢性肝炎导致肝纤维化和肝硬化。肝硬化是全球发病率和死亡率的主要原因。巨噬细胞在纤维化进展和逆转中起着关键作用。然而，决定成纤维细胞与纤维溶解巨噬细胞功能的信号仍然定义不明确。我们研究了白细胞介素 4 受体α（IL-4Rα）在肝纤维化进展和逆转中的作用，IL-4Rα 是巨噬细胞极化的潜在中央开关。我们证明，炎症性单核细胞浸润和肝纤维化在一般 IL-4Rα 以及巨噬细胞特异性 IL-4Rα（IL-4Rα）小鼠中均受到抑制。然而，IL-4Rα 的缺失会延迟自发性纤维化的逆转。使用 IL-4Rα 特异性反义寡核苷酸进行药理学干预复制了这些结果。延迟的解决与 M2 型驻留巨噬细胞的丢失有关，这些巨噬细胞通过 IL-4 和 IL-13 介导的磷酸化 STAT6 激活分泌 MMP-12。我们得出结论，IL-4Rα 信号以依赖于上下文的方式调节巨噬细胞功能的极化。因此，巨噬细胞极化的药理学靶向需要针对特定疾病阶段的治疗策略。
通过 IL-4Rα 进行替代（M2 型）巨噬细胞激活可促进肝炎症和纤维化进展，但可加速纤维化逆转。这表明 M2 型巨噬细胞具有依赖于上下文的、相反的作用。在逆转过程中，IL-4Rα 通过 STAT6 诱导纤维溶解 MMP，特别是 MMP-12。肝特异性反义寡核苷酸可有效阻断 IL-4Rα 的表达并减轻纤维化进展。
