NFκB sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles.
NFκB sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles.
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DOI：
10.1002/jbm.a.36504
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Goodman SB
中科院分区：
文献类型：
--
作者：
Lin T;Kohno Y;Huang JF;Romero-Lopez M;Pajarinen J;Maruyama M;Nathan K;Yao Z;Goodman SB
全关节置换术（TJR）是治疗终末期关节炎患者的一种非常有效的方法。促炎性巨噬细胞（M1）介导磨损颗粒相关炎症和骨丢失。抗炎巨噬细胞（M2）有助于解决组织损伤和促进骨再生。间充质干细胞（MSC）为基础的治疗减轻M1为主的炎症反应，并有利地调节骨重建过程。在本研究中，在巨噬细胞/MSC共培养系统中比较了1）未修饰的MSC，2）经NFκB刺激配体（脂多糖+TNFα）预处理的MSC，3）分泌IL-4作为对NFκB活化的应答的遗传修饰的MSC（NFκ B-IL 4）的免疫调节能力。使用无菌或LPS污染的超高分子量聚乙烯（UHMWPE）颗粒诱导巨噬细胞的促炎反应。污染颗粒诱导M1标志物表达（TNFα、IL 1 β和iNOS），而NFκ B-IL 4 MSC将巨噬细胞从M1表型调节为更有利的M2表型（精氨酸酶1/Arg 1和CD 206高）。NFκ B-IL 4 MSCs经污染颗粒处理后，IL 4分泌量明显增加。与NFκ B-IL 4 MSC相比，预处理或未处理的MSC对巨噬细胞中Arg 1和CD 206的诱导作用可以忽略不计。我们的研究结果表明，NFκ B-IL 4 MSC具有“按需”免疫调节能力，以减轻磨损颗粒相关的炎症，且副作用最小。
Total joint replacement (TJR) is a highly effective treatment for patients with end-stage arthritis. Pro-inflammatory macrophages (M1) mediate wear particle-associated inflammation and bone loss. Anti-inflammatory macrophages (M2) help resolve tissue damage and favor bone regeneration. Mesenchymal stem cell (MSC)-based therapy mitigates the M1 dominated inflammatory reaction and favorably modulates the bone remodeling process. In the current study, the immunomodulating ability of 1) unmodified MSCs, 2) MSCs preconditioned by NFκB stimulating ligands (lipopolysaccharide plus TNFα), and 3) genetically modified MSCs that secrete IL-4 as a response to NFκB activation (NFκB-IL4) was compared in a macrophage/MSC co-culture system. Sterile or LPS-contaminated ultra-high molecular weight polyethylene (UHMWPE) particles were used to induce the pro-inflammatory responses in the macrophages. Contaminated particles induced M1 marker expression (TNFα, IL1β, and iNOS), while NFκB-IL4 MSCs modulated the macrophages from an M1 phenotype into a more favorable M2 phenotype (Arginase 1/Arg1 and CD206 high). The IL4 secretion by NFκB-IL4 MSCs was significantly induced by the contaminated particles. The induction of Arg1 and CD206 in macrophages via the preconditioned or naïve MSCs was negligible when compared with NFκB-IL4 MSC. Our findings indicated that NFκB-IL4 MSCs have the “on-demand” immunomodulatory ability to mitigate wear particle-associated inflammation with minimal adverse effects.
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影响因子：
4.9
作者：
Pajarinen, Jukka;Tamaki, Yasunobu;Antonios, Joseph K.;Lin, Tzu-Hua;Sato, Taishi;Yao, Zhenyu;Takagi, Michiaki;Konttinen, Yrjo T.;Goodman, Stuart B.
通讯作者：
Goodman, Stuart B.
影响因子：
7.5
作者：
Lin T;Pajarinen J;Nabeshima A;Lu L;Nathan K;Jämsen E;Yao Z;Goodman SB
通讯作者：
Goodman SB
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.4
作者：
Fischer, JE;Johnson, JE;Graham, BS
通讯作者：
Graham, BS
影响因子：
9.7
作者：
Lin TH;Pajarinen J;Sato T;Loi F;Fan C;Córdova LA;Nabeshima A;Gibon E;Zhang R;Yao Z;Goodman SB
通讯作者：
Goodman SB