Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke.
Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke.
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DOI：
10.1186/s12974-018-1188-3
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发表时间：
2018-05-17
影响因子：
9.3
通讯作者：
McCullough LD
中科院分区：
文献类型：
--
作者：
Chauhan A;Hudobenko J;Al Mamun A;Koellhoffer EC;Patrizz A;Ritzel RM;Ganesh BP;McCullough LD
转化生长因子-β-活化激酶1 （TAK1）的激活发生在脑卒中后，并导致脑损伤加重。TAK1参与先天和适应性免疫反应，但它具有不同的炎症作用，这取决于它被激活的细胞类型。脑卒中后骨髓细胞大量浸润；然而，髓系TAK1在脑缺血中的作用目前尚不清楚。我们假设髓细胞特异性的TAK1缺失可以保护缺血性脑损伤。髓系TAK1ΔM和野生型（WT）小鼠进行大脑中动脉闭塞（MCAo）。脑卒中后3天观察脑浸润和脾免疫细胞的变化。脑卒中后第3天和第7天评估梗死面积和行为缺陷。TAK1ΔM小鼠的梗死面积明显减小（p < 0.01），尽管脑血流量减少，但行为缺陷较轻。流式细胞术显示TAK1ΔM小鼠脾单核细胞和中性粒细胞的频率增加（p < 0.05），脾CD3+ T细胞（p < 0.01）和CD19+ B细胞（p = 0.06）减少。卒中后3天，TAK1ΔM和WT小鼠的脑浸润免疫细胞数量均显著增加（p < 0.05）。然而，与WT中风小鼠相比，中风后TAK1ΔM的浸润性CD45hi免疫细胞计数显著减少（p < 0.05），浸润性单核细胞明显减少（p < 0.001）。此外，与野生型小鼠相比，TAK1ΔM中风小鼠大脑中CD49d+单核细胞显著减少。重要的是，TAK1ΔM MCAo小鼠在中风后第7天的梗死面积较小，行为结果也有所改善。我们的研究结果显示，髓系TAK1的缺失导致梗死面积缩小，炎症高峰期（第3天）的功能结果得到改善，脑浸润免疫细胞（主要是单核细胞）减少。髓系TAK1缺失在MCAo后7天也具有保护作用，反映了髓系TAK1在缺血性损伤进展中的不利作用。本文的在线版本（10.1186/s12974-018-1188-3）包含补充材料，可供授权用户使用。
Activation of transforming growth factor-β-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which it is activated. There is a robust infiltration of myeloid cells after stroke; however, the contribution of myeloid TAK1 to cerebral ischemia is currently unknown. We hypothesized that myeloid-specific deletion of TAK1 would protect against ischemic brain injury. Myeloid TAK1ΔM and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAo). Brain-infiltrating and splenic immune cells were evaluated at 3 days after stroke. Assessment of infarct size and behavioral deficits were performed on days 3 and 7 post-stroke. Infarcts were significantly smaller in TAK1ΔM mice (p < 0.01), and behavioral deficits were less severe despite equivalent reduction in cerebral blood flow. Flow cytometry demonstrated an increase in the frequency of splenic monocytes and neutrophils (p < 0.05) and a decrease in splenic CD3+ T (p < 0.01) and CD19+ B (p = 0.06) cells in TAK1ΔM mice compared to WT at baseline. Three days after stroke, a significant increase in the number of brain-infiltrating immune cell was observed in both TAK1ΔM (p < 0.05) and WT (p < 0.001) mice compared to their respective shams. However, there was a significant decrease in the infiltrating CD45hi immune cell counts (p < 0.05), with a pronounced reduction in infiltrating monocytes (p < 0.001) in TAK1ΔM after stroke compared to WT stroke mice. Additionally, a significant reduction in CD49d+ monocytes was seen in the brains of TAK1ΔM stroke mice compared to wild-type mice. Importantly, TAK1ΔM MCAo mice had smaller infarcts and improved behavioral outcomes at day 7 post-stroke. Our results showed that deletion of myeloid TAK1 resulted in smaller infarcts and improved functional outcomes at the peak of inflammation (day 3) and a reduction in brain-infiltrating immune cells that were primarily monocytes. Myeloid TAK1 deletion was also protective at 7 days post MCAo, reflecting a detrimental role of myeloid TAK1 in the progression of ischemic injury. The online version of this article (10.1186/s12974-018-1188-3) contains supplementary material, which is available to authorized users.
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DOI：
10.4049/jimmunol.0803357
发表时间：
2009-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kumar M;Makonchuk DY;Li H;Mittal A;Kumar A
通讯作者：
Kumar A
影响因子：
14.5
作者：
Cho, Ik-Hyun;Hong, Jinpyo;Lee, Sung Joong
通讯作者：
Lee, Sung Joong
影响因子：
4.8
作者：
McCullough, LD;Zeng, ZY;Ronnett, GV
通讯作者：
Ronnett, GV
影响因子：
8.3
作者：
Hammond MD;Ambler WG;Ai Y;Sansing LH
通讯作者：
Sansing LH
影响因子：
3.7
作者：
Lamothe, Betty;Lai, YunJu;Darnay, Bryant G.
通讯作者：
Darnay, Bryant G.