Alpha defensin-1 attenuates surgically induced osteoarthritis in association with promoting M1 to M2 macrophage polarization
Alpha defensin-1 attenuates surgically induced osteoarthritis in association with promoting M1 to M2 macrophage polarization
复制标题
Alpha defensin-1 可减轻手术诱发的骨关节炎，并促进 M1 至 M2 巨噬细胞极化
DOI：
10.1016/j.joca.2021.04.006
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发表时间：
2021-06-17
影响因子：
7
通讯作者：
Huang, Z. Y.
中科院分区：
文献类型：
--
作者：
Xie, J. W.;Wang, Y.;Huang, Z. Y.
目的：巨噬细胞在骨关节炎（OA）的发病机制中起重要作用。我们的目的是确定α-防御素-1对巨噬细胞极化和因此OA的影响。研究方法：通过流式细胞术评估OA滑膜组织和滑液中M1（CD 68 + CD 16 + CD 206-）和M2（CD 68 + CD 206 + CD 16-）巨噬细胞的存在。将M0、M1和M2巨噬细胞与OA软骨细胞共培养，以确定其对软骨形成表型的影响。通过流式细胞术、RT-PCR和RNA测序评估THP-1活化的单核细胞响应于α-防御素-1从M1到M2的极化。在大鼠踝关节/韧带损伤（MLI）模型中评估关节内α-防御素-1的体内作用。结果如下：在人OA滑膜组织（平均差异26.1% [13.6-38.6%]，P < 0.001）和液体（平均差异10.5% [5.0-16.1%]，P = 0.003）中，M1的数量超过M2极化的巨噬细胞。10 ng/mL α-防御素-1最有效地促进体外M1向M2极化。与未处理的巨噬细胞相比，α-防御素-1极化的巨噬细胞基于COL 2A 1、ACN、MMP 3、MMP 13和ADAMTS 5的表达将共培养的OA软骨细胞从促分解代谢状态修饰为促合成代谢（再生样）状态。关节内α-防御素-1降低了MLI大鼠模型中软骨损伤和滑膜炎的严重程度。RNAseq分析表明，在软骨保护性α-防御素-1作用机制中存在胰岛素和Toll样受体信号传导途径。结论：α-防御素-1在体外促进M1向M2巨噬细胞极化，通过M2巨噬细胞极化间接对软骨细胞具有有益作用，并且在体内减轻OA的严重程度，这表明其可能是OA的候选治疗。(c)2021国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
Objective: Macrophages play an important part in the pathogenesis of osteoarthritis (OA). Our objective was to determine the effects of a-defensin-1 on macrophage polarization and consequently OA. Methods: OA synovial tissue and synovial fluid were assessed for the presence of M1 (CD68+CD16+CD206-) and M2 (CD68+CD206+CD16-) macrophages by flow cytometry. M0, M1, and M2 macrophages were co-cultured with OA chondrocytes to determine their influence on chondrogenic phenotype. Polarization of THP-1 activated monocytes from M1 to M2 in response to a-defensin-1 was evaluated by flow cytometry, RT-PCR and RNA sequencing. Effects of intra-articular a-defensin-1 in vivo were evaluated in a rat meniscal/ligamentous injury (MLI) model. Results: The quantity of M1 exceeded M2 polarized macrophages in human OA synovial tissue (mean difference 26.1% [13.6-38.6%], P < 0.001) and fluid (mean difference 10.5% [5.0-16.1%], P = 0.003). M1 to M2 polarization in vitro was most effectively promoted with 10 ng/mL a-defensin-1. Compared with untreated macrophages, the a-defensin-1 polarized macrophages modified co-cultured OA chondrocytes from a pro-catabolic state to a pro-anabolic (regenerative-like) state based on expression of COL2A1, ACN, MMP3, MMP13 and ADAMTS5. Intra-articular a-defensin-1 decreased severity of cartilage damage and synovitis in the MLI rat model. RNAseq analyses suggested insulin and Toll-like receptor signaling pathways in the chondroprotective a-defensin-1 mechanism of action. Conclusion: a-defensin-1 promotes M1 to M2 macrophage polarization in vitro, has beneficial effects on chondrocytes indirectly via M2 macrophage polarization, and attenuates the severity of OA in vivo, suggesting it might be a candidate treatment for OA. (c) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.