Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype
Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype
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DOI：
10.1074/jbc.m113.479584
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发表时间：
2013-09-06
影响因子：
4.8
通讯作者：
Tseng, Scheffer C. G.
中科院分区：
文献类型：
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作者：
He, Hua;Zhang, Suzhen;Tseng, Scheffer C. G.
尽管已知羊膜具有抗炎作用，但其作用机制在很大程度上仍然未知。从人羊膜中纯化的HC-HA复合物（HC-HA）由高分子量的透明质酸（HA）共价连接至α-胰蛋白酶间抑制剂的重链（HC）1组成。在这项研究中，我们表明，可溶性HC-HA还含有五聚环蛋白3，并诱导甲酰基-Met-Leu-Phe或LPS激活的中性粒细胞和LPS激活的巨噬细胞的凋亡，而不影响静息细胞。这种增强的细胞凋亡是由LPS激活的巨噬细胞的HC-HA结合引起的细胞粘附、扩散和增殖的抑制以及防止粘附到塑料表面引起的。首先，可溶性HC-HA促进静息巨噬细胞中凋亡中性粒细胞的吞噬作用，而固定化HC-HA促进LPS激活的巨噬细胞的吞噬作用。在伴随的LPS刺激下，固定的HC-HA而不是HA通过下调IRF 5蛋白并阻止其核定位以及通过下调IL-12、TNF-α和NO合酶2使巨噬细胞向M2表型极化。此外，IL-10、TGF-β 1、过氧化物酶体增殖物激活受体γ、LIGHT（TNF超家族14）和鞘氨醇激酶-1上调，并且这种M2极化依赖于TLR连接。总的来说，这些数据表明HC-HA是一种不同于HA的独特基质组分，并使用多种机制抑制M1，同时促进M2表型。HC-HA的这种抗炎作用对于促进由M1至M2表型的不成功转变而加重的疾病中的伤口愈合是高度期望的。
Despite the known anti-inflammatory effect of amniotic membrane, its action mechanism remains largely unknown. HC-HA complex (HC-HA) purified from human amniotic membrane consists of high molecular weight hyaluronic acid (HA) covalently linked to the heavy chain (HC) 1 of inter-alpha-trypsin inhibitor. In this study, we show that soluble HC-HA also contained pentraxin 3 and induced the apoptosis of both formyl-Met-Leu-Phe or LPS-activated neutrophils and LPS-activated macrophages while not affecting the resting cells. This enhanced apoptosis was caused by the inhibition of cell adhesion, spreading, and proliferation caused by HC-HA binding of LPS-activated macrophages and preventing adhesion to the plastic surface. Preferentially, soluble HC-HA promoted phagocytosis of apoptotic neutrophils in resting macrophages, whereas immobilized HC-HA promoted phagocytosis in LPS-activated macrophages. Upon concomitant LPS stimulation, immobilized HC-HA but not HA polarized macrophages toward the M2 phenotype by down-regulating IRF5 protein and preventing its nuclear localization and by down-regulating IL-12, TNF-alpha, andNOsynthase 2. Additionally, IL-10, TGF-beta 1, peroxisome proliferator-activated receptor gamma, LIGHT (TNF superfamily 14), and sphingosine kinase-1 were up-regulated, and such M2 polarization was dependent on TLR ligation. Collectively, these data suggest that HC-HA is a unique matrix component different from HA and uses multiple mechanisms to suppress M1 while promoting M2 phenotype. This anti-inflammatory action of HC-HA is highly desirable to promote wound healing in diseases heightened by unsuccessful transition from M1 to M2 phenotypes.