Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) proteins and enzymes, especially fibrillary collagens, and represents a major cause of morbidity and mortality worldwide. Lysyl oxidases (LOXs) drive covalent crosslinking of collagen fibers, thereby promoting stabilization and accumulation of liver fibrosis while limiting its resolution. Here we show in a carbon tetrachloride (CCl4)-induced liver fibrosis murine model that treatment with a novel anti-lysyl oxidase like 2 (LOXL2) neutralizing antibody, which targets extracellular LOXL2, significantly improves fibrosis resolution. LOXL2 inhibition following the onset of fibrosis accelerated and augmented collagen degradation. This was accompanied by increased localization of reparative monocyte-derived macrophages (MoMFs) in the proximity of fibrotic fibers and their representation in the liver. These cells secreted collagenolytic matrix metalloproteinases (MMPs) and, in particular, the membrane-bound MT1-MMP (MMP-14) collagenase. Inducible and selective ablation of infiltrating MoMFs negated the increased "on-fiber" accumulation of MMP-14-expressing MoMFs and the accelerated collagenolytic activity observed in the anti-LOXL2-treated mice. Many studies of liver fibrosis focus on preventing the progression of the fibrotic process. In contrast, the therapeutic mechanism of LOXL2 inhibition presented herein aims at reversing existing fibrosis and facilitating endogenous liver regeneration by paving the way for collagenolytic macrophages.

中文翻译：

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LOXL2抑制为肝纤维化中巨噬细胞介导的胶原降解铺平了道路。

肝纤维化的特征在于细胞外基质（ECM）蛋白和酶（尤其是原纤维胶原）的过度积累，并且是全世界发病率和死亡率的主要原因。赖氨酰氧化酶（LOXs）驱动胶原纤维的共价交联，从而促进肝纤维化的稳定和积累，同时限制了其分辨率。在这里，我们在四氯化碳（CCl4）诱导的小鼠肝纤维化小鼠模型中显示，靶向细胞外LOXL2的新型抗赖氨酰氧化酶（如2）（LOXL2）中和抗体可以显着提高纤维化分辨率。纤维化发作后对LOXL2的抑制促进并增加了胶原蛋白的降解。这伴随着修复性单核细胞衍生的巨噬细胞（MoMF）在纤维化纤维附近的定位及其在肝脏中的表达增加。这些细胞分泌胶原蛋白水解基质金属蛋白酶（MMP），尤其是膜结合MT1-MMP（MMP-14）胶原酶。诱导性和选择性消融浸润的MoMFs消除了在抗LOXL2处理的小鼠中观察到的MMP-14表达MoMFs在纤维上积累的增加和胶原蛋白水解活性的提高。肝纤维化的许多研究集中于防止纤维化过程的进展。相反，本文呈现的LOXL2抑制的治疗机制旨在通过铺平胶原蛋白分解巨噬细胞的方式来逆转现有的纤维化并促进内源性肝再生。