Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver.
Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver.
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DOI：
10.1016/j.jcmgh.2022.01.015
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发表时间：
2022
影响因子：
7.2
通讯作者：
Tanabe, Kenneth K.
中科院分区：
文献类型：
--
作者：
Sojoodi, Mozhdeh;Erstad, Derek J.;Barrett, Stephen C.;Salloum, Shadi;Zhu, Shijia;Qian, Tongqi;Colon, Selene;Gale, Eric M.;Jordan, Veronica Clavijo;Wang, Yongtao;Li, Shen;Ataeinia, Bahar;Jalilifiroozinezhad, Sasan;Lanuti, Michael;Zukerberg, Lawrence;Caravan, Peter;Hoshida, Yujin;Chung, Raymond T.;Bhave, Gautam;Lauer, Georg M.;Fuchs, Bryan C.;Tanabe, Kenneth K.
在肝纤维化过程中，组织修复机制用高度稳定的细胞外基质蛋白替代坏死组织。细胞外基质的稳定性影响组织恢复的速度。在这里，我们研究了过氧化物酶（PXDN）的表达和功能，PXDN是一种过氧化物酶，在肝纤维化进展和消退过程中使用过氧化氢交联IV型胶原。分析肝纤维化小鼠模型和肝硬化患者肝脏和血清中PXDN的表达。Pxdn-/-和Pxdn+/+小鼠用四氯化碳处理6周以产生毒素诱导的纤维化，或用胆碱缺乏的L-氨基酸限定的高脂肪饮食喂养16周以产生非酒精性脂肪性肝病纤维化。分析肝组织学、定量实时聚合酶链反应、胶原含量、流式细胞术和免疫细胞免疫染色、RNA测序和肝功能检查。使用氧化还原活性铁复合物Fe-PyC 3A进行肝脏活性氧（ROS）的体内成像。在人和小鼠的纤维化组织中，PXDN由星状细胞表达并分泌到纤维化区域。在非酒精性脂肪性肝病患者中，血清PXDN水平显著升高。在两种小鼠肝纤维化模型中，PXDN缺乏导致单核细胞和促纤维溶解巨噬细胞募集到纤维化带中升高，并导致交联胶原的积累减少。在Pxdn-/-小鼠中，胶原纤维组织松散，这是一种非典型表型，在巨噬细胞耗竭后是可逆的。观察到Pxdn-/-肝脏中升高的ROS，其可导致缺氧信号级联的激活，并可影响参与巨噬细胞极化的信号通路，例如经由NF-kB的TNF-α。Pxdn-/-小鼠的纤维化消退与胶原含量的显著降低和肝功能的改善相关。PXDN缺乏与增加的ROS水平和缺氧的肝脏微环境相关，其可以调节促消退巨噬细胞的募集和编程。我们的数据暗示了肝纤维化过程中肝脏微环境在巨噬细胞编程中的重要性，并提出了一种新的途径，涉及瘢痕组织的解决。
During liver fibrosis, tissue repair mechanisms replace necrotic tissue with highly stabilized extracellular matrix proteins. Extracellular matrix stabilization influences the speed of tissue recovery. Here, we studied the expression and function of peroxidasin (PXDN), a peroxidase that uses hydrogen peroxide to cross-link collagen IV during liver fibrosis progression and regression. Mouse models of liver fibrosis and cirrhosis patients were analyzed for the expression of PXDN in liver and serum. Pxdn-/- and Pxdn+/+ mice were either treated with carbon tetrachloride for 6 weeks to generate toxin-induced fibrosis or fed with a choline-deficient L-amino acid-defined high-fat diet for 16 weeks to create nonalcoholic fatty liver disease fibrosis. Liver histology, quantitative real-time polymerase chain reaction, collagen content, flowcytometry and immunostaining of immune cells, RNA-sequencing, and liver function tests were analyzed. In vivo imaging of liver reactive oxygen species (ROS) was performed using a redox-active iron complex, Fe-PyC3A. In human and mouse cirrhotic tissue, PXDN is expressed by stellate cells and is secreted into fibrotic areas. In patients with nonalcoholic fatty liver disease, serum levels of PXDN increased significantly. In both mouse models of liver fibrosis, PXDN deficiency resulted in elevated monocyte and pro-fibrolysis macrophage recruitment into fibrotic bands and caused decreased accumulation of cross-linked collagens. In Pxdn-/- mice, collagen fibers were loosely organized, an atypical phenotype that is reversible upon macrophage depletion. Elevated ROS in Pxdn-/- livers was observed, which can result in activation of hypoxic signaling cascades and may affect signaling pathways involved in macrophage polarization such as TNF-a via NF-kB. Fibrosis resolution in Pxdn-/- mice was associated with significant decrease in collagen content and improved liver function. PXDN deficiency is associated with increased ROS levels and a hypoxic liver microenvironment that can regulate recruitment and programming of pro-resolution macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest a novel pathway that is involved in the resolution of scar tissue.
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影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.
影响因子：
3.3
作者：
BERG, JT;LEE, ST;TSAN, MF
通讯作者：
TSAN, MF
影响因子：
3.5
作者：
Hanmer, Kerry L.;Mavri-Damelin, Demetra
通讯作者：
Mavri-Damelin, Demetra
影响因子：
7.7
作者：
Brown KL;Darris C;Rose KL;Sanchez OA;Madu H;Avance J;Brooks N;Zhang MZ;Fogo A;Harris R;Hudson BG;Voziyan P
通讯作者：
Voziyan P
影响因子：
13.5
作者：
Heymann, Felix;Peusquens, Julia;Tacke, Frank
通讯作者：
Tacke, Frank