Latent, Immunosuppressive Nature of Poly(lactic-co-glycolic acid) Microparticles
Latent, Immunosuppressive Nature of Poly(lactic-co-glycolic acid) Microparticles
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DOI：
10.1021/acsbiomaterials.7b00831
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发表时间：
2018-03-01
影响因子：
5.8
通讯作者：
Lewis, Jamal S.
中科院分区：
文献类型：
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作者：
Allen, Riley P.;Bolandparvaz, Amir;Lewis, Jamal S.
使用生物材料时空控制免疫细胞的激活是生物医学工程研究的前沿。随着越来越多的生物材料策略被用于免疫调节，了解生物可降解材料及其副产物的免疫原性对于定制免疫激活或抑制系统至关重要。聚（D，L-乳酸-共-乙醇酸）（PLGA），在组织工程和药物递送中最常研究的聚合物之一，先前已经描述了一方面作为免疫佐剂，另一方面作为非活化材料。在这项研究中，PLGA微粒（MP）对小鼠骨髓来源的树突状细胞（DC），获得性免疫的主要发起人的成熟状态的影响，进行了研究，以破译这种生物材料的免疫调节特性。用PLGA MP处理来自CS 7 BL/6小鼠的骨髓来源的DC导致这些细胞的成熟水平的时间依赖性降低，如通过阳性刺激分子MHCII、CD 80和CD 86的表达降低以及在用脂多糖（LPS）攻击后抵抗成熟的能力所定量的。此外，这种免疫抑制依赖于用于制造MP的PLGA的分子量，因为较高分子量的聚合物需要更长的孵育时间以产生相当的成熟分子的抑制。这些现象与DC/PLGA MP共培养期间细胞内和细胞外乳酸的增加相关，这被假定为观察到的免疫抑制背后的主要因素。我们的结果支持了这一假设，表明对LPS刺激的抵抗可能是由于PLGA MP衍生的乳酸抑制TK 1磷酸化的能力，从而阻止NF-κ B活化。这项工作是重要的，因为它开始阐明如何PLGA，一个突出的生物材料，具有广泛的应用范围从组织工程到制药，可以调节局部免疫环境，并提供工程PLGA利用其不断发展的免疫原性的见解。
Use of biomaterials to spatiotemporally control the activation of immune cells is at the forefront of biomedical engineering research. As more biomaterial strategies are employed for immunomodulation, understanding the immunogenicity of biodegradable materials and their byproducts is paramount in tailoring systems for immune activation or suppression. Poly(D,L-lactic-co-glycolic acid) (PLGA), one of the most commonly studied polymers in tissue engineering and drug delivery, has been previously described on one hand as an immune adjuvant, and on the other as a nonactivating material. In this study, the effect of PLGA microparticles (MPs) on the maturation status of murine bone marrow derived dendritic cells (DCs), the primary initiators of adaptive immunity, was investigated to decipher the immunomodulatory properties of this biomaterial. Treatment of bone marrow-derived DCs from CS7BL/6 mice with PLGA MPs led to a time dependent decrease in the maturation level of these cells, as quantified by decreased expression of the positive stimulatory molecules MHCII, CD80, and CD86 as well as the ability to resist maturation following challenge with lipopolysaccharide (LPS). Moreover, this immunosuppression was dependent on the molecular weight of the PLGA used to fabricate the MPs, as higher molecular weight polymers required longer incubation to produce comparable dampening of maturation molecules. These phenomena were correlated to an increase in lactic acid both intracellularly and extracellularly during DC/PLGA MP coculture, which is postulated to be the primary agent behind the observed immune inhibition. This hypothesis is supported by our results demonstrating that resistance to LPS stimulation may be due to the ability of PLGA MP-derived lactic acid to inhibit the phosphorylation of TAK1 and therefore prevent NF-kappa B activation. This work is significant as it begins to elucidate how PLGA, a prominent biomaterial with broad applications ranging from tissue engineering to pharmaceutics, could modulate the local immune environment and offers insight on engineering PLGA to exploit its evolving immunogenicity.