Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
Department of Imaging and Pathology, OMFS-IMPATH Research Group KU Leuven and Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium.
Front Immunol. 2024 Aug 2;15:1359497. doi: 10.3389/fimmu.2024.1359497. eCollection 2024.
SDF-1/CXCL12 is a unique chemotactic factor with multiple functions on various types of precursor cells, all carrying the cognate receptor CXCR4. Whereas individual biological functions of SDF-1/CXCL12 have been well documented, practical applications in medicine are insufficiently studied. This is explained by the complex multifunctional biology of SDF-1 with systemic and local effects, critical dependence of SDF-1 activity on aminoterminal proteolytic processing and limited knowledge of applicable modulators of its activity. We here present new insights into modulation of SDF-1 activity and by a macromolecular compound, chlorite-oxidized oxyamylose (COAM). COAM prevented the proteolytic inactivation of SDF-1 by two inflammation-associated proteases: matrix metalloproteinase-9/MMP-9 and dipeptidylpeptidase IV/DPPIV/CD26. The inhibition of proteolytic inactivation was functionally measured by receptor-mediated effects, including intracellular calcium mobilization, ERK1/2 phosphorylation, receptor internalization and chemotaxis of CXCR4-positive cells. Protection of SDF-1/CXCL12 against proteolysis was dependent on electrostatic COAM-SDF-1 interactions. By experiments in mice, we showed that the combination of COAM with SDF-1 delivered through physiological fibrin hydrogel had beneficial effect for the healing of skin wounds. Collectively, we show that COAM protects SDF-1 from proteolytic inactivation, maintaining SDF-1 biological activities. Thus, protection from proteolysis by COAM represents a therapeutic strategy to prolong SDF-1 bioavailability for wound healing applications.
基质细胞衍生因子 1（SDF-1）/CXCL12 是一种独特的趋化因子，对各种类型的前体细胞具有多种功能，所有这些前体细胞都携带同源受体 CXCR4。尽管 SDF-1/CXCL12 的单个生物学功能已得到充分证实，但在医学中的实际应用研究不足。这是由于 SDF-1 的复杂多功能生物学具有全身和局部效应，SDF-1 活性对氨基末端蛋白水解加工的关键依赖性以及对其活性适用调节剂的有限了解所导致的。我们在此介绍了一种新的见解，即通过一种大分子化合物——亚氯酸钠氧化的羟胺淀粉（COAM）来调节 SDF-1 的活性和稳定性。COAM 可防止两种炎症相关蛋白酶：基质金属蛋白酶-9（MMP-9）和二肽基肽酶 IV（DPPIV/CD26）对 SDF-1 的蛋白水解失活。通过受体介导的效应（包括细胞内钙动员、ERK1/2 磷酸化、受体内化和 CXCR4 阳性细胞的趋化性）来测量对蛋白水解失活的抑制作用，以功能方式进行测量。SDF-1/CXCL12 的保护免受蛋白水解依赖于静电 COAM-SDF-1 相互作用。通过在小鼠中的实验，我们表明 COAM 与通过生理纤维蛋白水凝胶输送的 SDF-1 结合对皮肤伤口的愈合具有有益的效果。总的来说，我们表明 COAM 可防止 SDF-1 发生蛋白水解失活，从而维持 SDF-1 的生物学活性。因此，COAM 对蛋白水解的保护代表了一种延长 SDF-1 生物利用度以用于伤口愈合应用的治疗策略。
