High and low molecular weight hyaluronic acid differentially influence macrophage activation.
High and low molecular weight hyaluronic acid differentially influence macrophage activation.
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DOI：
10.1021/acsbiomaterials.5b00181
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发表时间：
2015-07-13
影响因子：
5.8
通讯作者：
Gemeinhart RA
中科院分区：
文献类型：
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作者：
Rayahin JE;Buhrman JS;Zhang Y;Koh TJ;Gemeinhart RA
巨噬细胞表现出表型多样性，允许在维持生理稳态的广泛作用。透明质酸是细胞外基质的主要糖胺聚糖，已显示具有基于其分子量的差异信号传导。考虑到这一点，本研究的主要目的是阐明透明质酸分子量对巨噬细胞活化和重编程的作用。巨噬细胞活化的变化进行了评估，活化状态选择性标记物测量，特别是定量的真实的时间聚合酶链反应，和细胞因子酶联免疫测定，巨噬细胞治疗后，不同分子量的透明质酸在四种条件下：静息状态，同时与经典的激活，炎症涉及经典或替代激活的巨噬细胞。无论初始极化状态如何，低分子量透明质酸诱导了经典的激活样状态，这通过促炎基因（包括nos 2、tnf、il 12 b和cd 80）的上调以及一氧化氮和TNF-α的分泌增强得到证实。高分子量的透明质酸促进了一种类似于交替激活的状态，这一点可以通过上调促分解基因转录（包括arg 1、il 10和mrc 1）和增强的促分解酶活性来证实。总体而言，我们的观察结果表明，巨噬细胞发生依赖于透明质酸分子量的表型变化，对应于（1）低分子量HA的促炎反应或（2）高分子量HA的促消退反应。这些观察结果带来了重要的进一步了解的影响，细胞外基质聚合物，特别是透明质酸，调节巨噬细胞的炎症反应。这些知识可用于指导含HA生物材料的设计，以更好地利用对HA的自然反应。
Macrophages exhibit phenotypic diversity permitting wide-ranging roles in maintaining physiologic homeostasis. Hyaluronic acid, a major glycosaminoglycan of the extracellular matrix, has been shown to have differential signaling based on its molecular weight. With this in mind, the main objective of this study was to elucidate the role of hyaluronic acid molecular weight on macrophage activation and reprogramming. Changes in macrophage activation were assessed by activation state selective marker measurement, specifically quantitative real time polymerase chain reaction, and cytokine enzyme-linked immunoassays, after macrophage treatment with differing molecular weights of hyaluronic acid under four conditions: the resting state, concurrent with classical activation, and following inflammation involving either classically or alternatively activated macrophages. Regardless of initial polarization state, low molecular weight hyaluronic acid induced a classically activated-like state, confirmed by up-regulation of pro-inflammatory genes, including nos2, tnf, il12b, and cd80, and enhanced secretion of nitric oxide and TNF-α. High molecular weight hyaluronic acid promoted an alternatively activated-like state, confirmed by up regulation of pro-resolving gene transcription, including arg1, il10, and mrc1, and enhanced arginase activity. Overall, our observations suggest that macrophages undergo phenotypic changes dependent on molecular weight of hyaluronan that correspond to either (1) pro-inflammatory response for low molecular weight HA or (2) pro-resolving response for high molecular weight HA. These observations bring significant further understanding of the influence of extracellular matrix polymers, hyaluronic acid in particular, on regulating the inflammatory response of macrophages. This knowledge can be used to guide the design of HA-containing biomaterials to better utilize the natural response to HAs.