Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12-independent manner and worsens tissue remodeling after myocardial infarction
Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12-independent manner and worsens tissue remodeling after myocardial infarction
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DOI：
10.1016/j.bbadis.2017.07.012
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发表时间：
2017-11-01
影响因子：
6.2
通讯作者：
Raucci, Angela
中科院分区：
文献类型：
--
作者：
Di Maggio, Stefania;Milano, Giuseppina;Raucci, Angela
心肌梗死（MI）是全球范围内的主要健康负担。细胞外高迁移率族蛋白1（HMGB 1）调节损伤后的组织愈合。HMGB 1的还原形式（fr-HMGB 1）通过CXCR 4结合CXCL 12发挥趋化活性，而二硫键形式（ds-HMGB 1）通过TLR 4诱导细胞因子表达。在此，我们评估了HMGB 1氧化还原形式和不可氧化突变体（3S）对人心肌成纤维细胞（hcFbs）功能和梗死后心脏重塑的作用。Fr-HMGB 1和3S，而不是ds-HMGB 1，通过Src激活促进hcFbs迁移，而没有HMGB 1氧化还原形式诱导增殖或炎症介质。3S在刺激hcFbs迁移和Src磷酸化方面比fr-HMGB 1更有效，在较低浓度和氧化条件下具有活性。值得注意的是，对这两种蛋白质的趋化性是CXCR 4依赖性的，但与fr-HMGB 1相反，3S不需要CXCL 12，因为hcFbs迁移在CXCL 12/CXCR 4抑制剂AMD 3100或抗CXCL 12抗体存在下持续存在。有趣的是，3S与CXCR 4相互作用，并诱导与CXCL 12不同的受体构象。经历MI并接受3S的小鼠表现出不利的LV重塑，这是由于大量肌成纤维细胞促进了过度的胶原沉积。相反，fr-HMGB 1改善心脏功能，增强新生血管生成，减少梗死面积和纤维化。总之，我们的研究结果表明，非氧化HMGB 1诱导持续的心脏成纤维细胞迁移，尽管环境的氧化还原状态，并通过改变CXCL 12/CXCR 4轴。这会影响梗死后适当的心脏重塑。
Myocardial infarction (MI) is a major health burden worldwide. Extracellular High mobility group box 1 (HMGB1) regulates tissue healing after injuries. The reduced form of HMGB1 (fr-HMGB1) exerts chemotactic activity by binding CXCL12 through CXCR4, while the disulfide form, (ds-HMGB1), induces cytokines expression by TLR4. Here, we assessed the role of HMGB1 redox forms and the non-oxidizable mutant (3S) on human cardiac fibroblast (hcFbs) functions and cardiac remodeling after infarction.Among HMGB1 receptors, hcFbs express CXCR4. Fr-HMGB1 and 3S, but not ds-HMGB1, promote hcFbs migration through Src activation, while none of HMGB1 redox forms induces proliferation or inflammatory mediators. 3S is more effective than fr-HMGB1 in stimulating hcFbs migration and Src phosphorylation being active at lower concentrations and in oxidizing conditions. Notably, chemotaxis toward both proteins is CXCR4-dependent but, in contrast to fr-HMGB1, 3S does not require CXCL12 since hcFbs migration persists in the presence of the CXCL12/CXCR4 inhibitor AMD3100 or an anti-CXCL12 antibody. Interestingly, 3S interacts with CXCR4 and induces a different receptor conformation than CXCL12. Mice undergoing MI and receiving 3S exhibit adverse LV remodeling owing to an excessive collagen deposition promoted by a higher number of myofibroblasts. On the contrary, fr-HMGB1 ameliorates cardiac performance enhancing neoangiogenesis and reducing the infarcted area and fibrosis.Altogether, our results demonstrate that non-oxidizable HMGB1 induce a sustained cardiac fibroblasts migration despite the redox state of the environment and by altering CXCL12/CXCR4 axis. This affects proper cardiac remodeling after an infarction.