Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1
Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1
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DOI：
10.1172/jci.insight.136706
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发表时间：
2020-08-06
期刊：
影响因子：
8
通讯作者：
Hajishengallis, George
中科院分区：
文献类型：
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作者：
Maekawa, Tomoki;Tamura, Hikaru;Hajishengallis, George
大环内酯类抗生素具有抗炎作用，但对其免疫调节机制知之甚少。在这项研究中，我们使用了两种不同的小鼠粘膜炎性疾病模型(脂多糖诱导的急性肺损伤和结扎诱导的牙周炎)，证明红霉素(ERM)的抗炎作用是通过上调分泌的动态平衡蛋白发育内皮基因-1(DEL-1)来实现的。与内皮细胞来源的Del-1的抗中性粒细胞募集作用一致，ERM以Del-1依赖的方式抑制中性粒细胞在肺和牙周组织的渗透。虽然ERM(但不是其他抗生素，如交沙霉素和青霉素)可以防止致命的肺部炎症和炎性牙周骨丢失，但ERM的这些保护作用在DELL缺陷小鼠中被取消。ERM通过与生长激素促分泌素受体相互作用，激活人肺微血管内皮细胞JAK2，诱导DEL1转录，该转录由MAPK p38介导，并依赖于CCAAT/增强子结合蛋白β。此外，ERM逆转了IL-17对Del-1转录的抑制，这种抑制不仅依赖于JAK2，还依赖于P13K/AKT信号。由于在炎症条件下，随着年龄的增长，Del-1的水平会严重降低，ERM上调Del-1的能力可能会导致一种新的治疗炎症和衰老相关疾病的方法。
Macrolide antibiotics exert antiinflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using 2 distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the antiinflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein developmental endothelial locus-1 (DEL-1). Consistent with the anti-neutrophil recruitment action of endothelial cell-derived DEL-1, ERM inhibited neutrophil infiltration in the lungs and the periodontium in a DEL-1-dependent manner. Whereas ERM (but not other antibiotics, such as josamycin and penicillin) protected against lethal pulmonary inflammation and inflammatory periodontal bone loss, these protective effects of ERM were abolished in Dell-deficient mice. By interacting with the growth hormone secretagogue receptor and activating JAK2 in human lung microvascular endothelial cells, ERM induced DEL1 transcription that was mediated by MAPK p38 and was CCAAT/enhancer binding protein-beta dependent. Moreover, ERM reversed IL-17-induced inhibition of DEL-1 transcription, in a manner that was dependent not only on JAK2 but also on P13K/AKT signaling. Because DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may lead to a novel approach for the treatment of inflammatory and aging-related diseases.