Myeloid differentiation factor‐2 activates monocytes in patients with dilated cardiomyopathy
Myeloid differentiation factor‐2 activates monocytes in patients with dilated cardiomyopathy
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DOI：
10.1111/imm.13490
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发表时间：
2022-05
期刊：
影响因子：
6.4
通讯作者：
R. Feldtmann;Andreas Kümmel;B. Chamling;A. Strohbach;K. Lehnert;S. Gross;Lisa Loerzer;A. Riad;D. Lindner;D. Westermann;J. Fielitz;M. Dörr;S. Felix
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作者：
R. Feldtmann;Andreas Kümmel;B. Chamling;A. Strohbach;K. Lehnert;S. Gross;Lisa Loerzer;A. Riad;D. Lindner;D. Westermann;J. Fielitz;M. Dörr;S. Felix
髓样分化因子-2（MD-2）是Toll样受体4（TLR 4）的共受体，其血浆水平可独立预测扩张型心肌病（DCM）患者的死亡率。我们测试了MD-2激活单核细胞是否有助于DCM患者的免疫激活和炎症状态。我们发现25例新发DCM患者的MD-2血浆水平（1250 ± 80.7 ng/ml）高于25例年龄和性别匹配的健康对照（793.4 ± 52.0 ng/ml; p < 0.001）。从DCM患者中分离的单核细胞显示MD-2编码基因LY 96的表达更高（141.7 ± 12.4%; p = 0.006 vs.对照），NF-κB-活化增加。此外，与对照组相比，TLR 4激活剂脂多糖（LPS）导致DCM患者单核细胞中白细胞介素（IL）-6的增加更高（平均荧光强度：938.7 ± 151.0 vs. 466.9 ± 51.1; p = 0.005）。通过TLR 4-siRNA和NF-κ B-抑制证实，MD-2以TLR 4/NF-κ B-依赖性方式增加单核细胞样THP-1-细胞中的IL-6分泌。由于内皮细胞（EC）负责将单核细胞募集到炎症部位，因此用MD-2处理EC，导致Akt活化和单核细胞趋化蛋白-1（MCP-1）分泌增加。MD-2对EC的激活伴随着粘附分子CD 54、CD 106和CD 62 E的表达增加，导致单核细胞募集增加，而CD 54抑制则减弱了单核细胞募集。此外，在小鼠WT而非LY 96-KO骨髓源性巨噬细胞中，LPS增加了CD 54和CD 49 d/CD 29的量。MD-2通过TLR 4/NF-κB促进单核细胞的促炎状态和EC介导的单核细胞募集。MD-2血浆水平升高可能参与单核细胞相关炎症-促进DCM疾病进展。我们的研究结果表明，MD-2有助于增加单核细胞的炎症活性，并触发单核细胞募集到DCM中的EC。
Plasma levels of myeloid differentiation factor‐2 (MD‐2), a co‐receptor of toll‐like‐receptor 4 (TLR4), independently predict mortality in patients with dilated cardiomyopathy (DCM). We tested whether monocyte activation by MD‐2 contributes to immune activation and inflammatory status in DCM patients. We found increased MD‐2 plasma levels in 25 patients with recent‐onset DCM (1250 ± 80.7 ng/ml) compared to 25 age‐ and gender‐matched healthy controls (793.4 ± 52.0 ng/ml; p < 0.001). Monocytes isolated from DCM patients showed a higher expression (141.7 ± 12.4%; p = 0.006 vs. controls) of the MD‐2 encoding gene, LY96 and an increased NF‐κB‐activation. Further, the TLR4‐activator lipopolysaccharide (LPS) caused a higher increase in interleukin (IL)‐6 in monocytes from DCM patients compared to controls (mean fluorescence intensity: 938.7 ± 151.0 vs. 466.9 ± 51.1; p = 0.005). MD‐2 increased IL‐6 secretion in a TLR4/NF‐κB‐dependent manner in monocyte‐like THP‐1‐cells as demonstrated by TLR4‐siRNA and NF‐κB‐inhibition. Since endothelial cells (ECs) are responsible for recruiting monocytes to the site of inflammation, ECs were treated with MD‐2 leading to an activation of Akt and increased secretion of monocyte‐chemoattractant‐protein‐1 (MCP‐1). Activation of ECs by MD‐2 was accompanied by an increased expression of the adhesion molecules CD54, CD106 and CD62E, resulting in an increased monocyte recruitment, which was attenuated by CD54 inhibition. In addition, in murine WT but not LY96‐KO bone marrow‐derived macrophages LPS increased the amount of CD54 and CD49d/CD29. MD‐2 facilitates a pro‐inflammatory status of monocytes and EC‐mediated monocyte recruitment via TLR4/NF‐κB. Elevated MD‐2 plasma levels are possibly involved in monocyte‐related inflammation‐promoting disease progression in DCM. Our results suggest that MD‐2 contributes to increasing monocytic inflammatory activity and triggers the recruitment of monocytes to ECs in DCM.