Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium.
Int J Mol Sci. 2022 Aug 26;23(17):9715. doi: 10.3390/ijms23179715.
Ischemia-reperfusion injury (IRI) drives graft rejection and is the main cause of mortality after liver transplantation. During IRI, an intense inflammatory response marked by chemokine production and neutrophil recruitment occurs. However, few strategies are available to restrain this excessive response. Here, we aimed to interfere with chemokine function during IRI in order to disrupt neutrophil recruitment to the injured liver. For this, we utilized a potent glycosaminoglycan (GAG)-binding peptide containing the 30 C-terminal amino acids of CXCL9 (MIG30) that is able to inhibit the binding of chemokines to GAGs in vitro. We observed that mice subjected to IRI and treated with MIG30 presented significantly lower liver injury and dysfunction as compared to vehicle-treated mice. Moreover, the levels of chemokines CXCL1, CXCL2 and CXCL6 and of proinflammatory cytokines TNF-α and IL-6 were significantly reduced in MIG30-treated mice. These events were associated with a marked inhibition of neutrophil recruitment to the liver during IRI. Lastly, we observed that MIG30 is unable to affect leukocytes directly nor to alter the stimulation by either CXCL8 or lipopolysaccharide (LPS), suggesting that its protective properties derive from its ability to inhibit chemokine activity in vivo. We conclude that MIG30 holds promise as a strategy to treat liver IRI and inflammation.
缺血再灌注损伤（IRI）可导致移植物排斥，是肝移植后死亡的主要原因。在 IRI 期间，会发生强烈的炎症反应，其特征是趋化因子的产生和中性粒细胞的募集。然而，目前可用的策略很少能够抑制这种过度反应。在这里，我们旨在干预 IRI 期间趋化因子的功能，以破坏中性粒细胞向受损肝脏的募集。为此，我们利用了一种含有 CXCL9 30 个 C 末端氨基酸的强效糖胺聚糖（GAG）结合肽（MIG30），该肽能够抑制趋化因子与 GAG 体外结合。我们观察到，与 vehicle 治疗的小鼠相比，接受 IRI 治疗并给予 MIG30 的小鼠肝损伤和功能障碍明显降低。此外，MIG30 治疗的小鼠中趋化因子 CXCL1、CXCL2 和 CXCL6 以及促炎细胞因子 TNF-α 和 IL-6 的水平也显著降低。这些事件与 IRI 期间中性粒细胞向肝脏的募集明显抑制有关。最后，我们观察到 MIG30 不能直接影响白细胞，也不能改变 CXCL8 或脂多糖（LPS）的刺激作用，这表明其保护特性源自其在体内抑制趋化因子活性的能力。我们得出结论，MIG30 有望成为治疗肝 IRI 和炎症的一种策略。
