Mesenchymal stem cells suppress neuronal apoptosis and decrease IL-10 release via the TLR2/NFκB pathway in rats with hypoxic-ischemic brain damage.
Mesenchymal stem cells suppress neuronal apoptosis and decrease IL-10 release via the TLR2/NFκB pathway in rats with hypoxic-ischemic brain damage.
复制标题
DOI：
10.1186/s13041-015-0157-3
复制
发表时间：
2015-10-17
期刊：
影响因子：
3.6
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Gu Y;Zhang Y;Bi Y;Liu J;Tan B;Gong M;Li T;Chen J
缺氧缺血性脑损伤（HIBD）是导致婴儿死亡和儿童神经功能障碍的主要原因。许多研究表明，间充质干细胞（MSC）移植通过免疫调节促进HIBD后损伤组织生物学功能的恢复。本研究旨在阐明骨髓间充质干细胞通过关键效应因子Toll样受体2（TLR 2）和白细胞介素-10（IL-10）介导免疫调节的机制。我们发现HIBD大鼠脑内TLR 2的表达在HIBD后上调，MSC移植抑制TLR 2的表达和IL-10的释放，从而减轻HIBD大鼠的学习记忆障碍。用特异性TLR 2激动剂Pam 3CSK 4激活TLR 2后，学习记忆功能进一步受损，与未接受Pam 3CSK 4的HIBD大鼠相比，核因子κ B（NFκB B）和Bax表达水平以及IL-10释放水平显著增加。在体外实验中，我们发现MSC共培养下调了TLR 2/NFκB信号转导，抑制了缺氧缺糖（OGD）损伤的肾上腺嗜铬细胞瘤（PC 12）细胞Bax表达和IL-10分泌。此外，在存在或不存在MSC的情况下，在OGD损伤的PC 12细胞中，Pam 3CSK 4处理后NFκB和Bax表达以及IL-10释放增强，而siTLR 2处理后NFκB和Bax表达以及IL-10释放降低。我们的数据表明，TLR 2参与了HIBD，并且MSC通过减少IL-10释放的反馈机制抑制TLR 2/NFκB信号通路来减少HIBD大鼠的凋亡并改善学习记忆功能。这些发现强烈提示MSC移植通过抑制TLR 2/NFκB通路改善HIBD。
Hypoxic–ischemic brain damage (HIBD) is a major cause of infant mortality and neurological disability in children. Many studies have demonstrated that mesenchymal stem cell (MSC) transplantation facilitates the restoration of the biological function of injured tissue following HIBD via immunomodulation. This study aimed to elucidate the mechanisms by which MSCs mediate immunomodulation via the key effectors Toll-like receptor 2 (TLR2) and interleukin-10 (IL-10). We showed that TLR2 expression in the brain of HIBD rats was upregulated following HIBD and that MSC transplantation suppressed the expression of TLR2 and the release of IL-10, thereby alleviating the learning-memory deficits of HIBD rats. Following treatment with the specific TLR2 agonist Pam3CSK4 to activate TLR2, learning-memory function became further impaired, and the levels of nuclear factor kappa B (NFκB) and Bax expression and IL-10 release were significantly increased compared with those in HIBD rats that did not receive Pam3CSK4. In vitro, we found that MSC co-culture downregulated TLR2/NFκB signaling and repressed Bax expression and IL-10 secretion in oxygen and glucose deprivation (OGD)-injured adrenal pheochromocytoma (PC12) cells. Furthermore, NFκB and Bax expression and IL-10 release were enhanced following Pam3CSK4 treatment and were decreased following siTLR2 treatment in OGD-injured PC12 cells in the presence or absence of MSCs. Our data indicate that TLR2 is involved in HIBD and that MSCs decrease apoptosis and improve learning-memory function in HIBD rats by suppressing the TLR2/NFκB signaling pathway via a feedback mechanism that reduces IL-10 release. These findings strongly suggest that MSC transplantation improves HIBD via the inhibition of the TLR2/NFκB pathway.