Endogenous Uteroglobin as Intrinsic Anti-inflammatory Signal Modulates Monocyte and Macrophage Subsets Distribution Upon Sepsis Induced Lung Injury
Endogenous Uteroglobin as Intrinsic Anti-inflammatory Signal Modulates Monocyte and Macrophage Subsets Distribution Upon Sepsis Induced Lung Injury
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DOI：
10.3389/fimmu.2019.02276
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发表时间：
2019-10-01
影响因子：
7.3
通讯作者：
Relja, Borna
中科院分区：
文献类型：
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作者：
Janicova, Andrea;Becker, Nils;Relja, Borna
脓毒症是一种严重的临床疾病，可导致危及生命的器官功能障碍，治疗选择有限。限制过度炎症和促进抗炎反应的范例是一个简化的概念。然而，在感染早期缺乏固有的抗炎信号会导致免疫细胞的过度激活，包括单核细胞和巨噬细胞。有新的证据表明，内源性分子控制着这些机制。在这里，我们旨在识别和描述CL57BL/6N小鼠钝性胸外伤后盲肠结扎和穿刺后单核细胞和巨噬细胞亚群和肺损伤的动态变化。我们发现，早期系统性和活化的Ly6C(+)CD11b(+)CD45(+)Ly6G（-）单核细胞的增加与它们向肺部迁移的增加是平行的。在血液、肺和支气管肺泡灌洗液（BALF）中，促炎Ly6C（高）CD11b(+)CD45(+)Ly6G（-）单核细胞与巡逻Ly6C（低）CD11b(+)CD45(+)Ly6G（-）单核细胞的比例显著增加，提示在脓毒症早期发展过程中早期向炎症表型过渡。与单核细胞相似，促炎Ly6C（高）CD45(+)F4/80（+）巨噬细胞在肺和BALF中水平升高，而组织修复Ly6C（低）CD45(+)F4/80（+）巨噬细胞在BALF中水平下降。血液中炎症介质tnf - α和MCP-1水平升高，肺和BALF中的RAGE水平升高，它们除了通过细胞募集促进炎症外，还可能分别促进单核细胞和巨噬细胞向促炎表型极化。子宫红蛋白的中和增加了促炎细胞因子水平，激活了炎症表型并将其募集到肺部；与脓毒症小鼠肺损伤增加同时发生。在体外实验中，证实了子宫红蛋白对单核细胞功能的影响，包括迁移行为、tgf - β 1表达、细胞毒性和活力。这些结果强调了内源性子宫红蛋白在脓毒症诱导的早期肺损伤中作为内在抗炎信号的重要作用，它模块了早期单核细胞/巨噬细胞驱动的炎症。钝性胸部损伤是继重大创伤之后的第三大死亡原因，持续过度的促炎免疫反应导致继发性并发症（如败血症）的高风险，治疗选择有限。在小鼠胸部创伤和随后的盲肠结扎和穿刺双重打击创伤中，我们研究了血液、肺和支气管肺泡灌洗液（BALF）中巡逻Ly6C（低）CD11b(+)CD45(+)Ly6G（-）单核细胞和Ly6C（低）CD45(+)F4/80（+）巨噬细胞向促炎Ly6C（高）CD11b(+)CD45(+)Ly6G（-）单核细胞和Ly6C（高）CD45(+)F4/80（+）细胞的细胞因子谱、肺上皮完整性和表型转移。促炎介质和表型升高，子宫红蛋白中和导致进一步增加。BALF总蛋白水平增高提示呼吸上皮渗漏。在体外，子宫红蛋白抑制了单核细胞的迁移能力和tgf - β 1的表达，但不影响细胞的生存能力。这些结果强调了内源性子宫红蛋白在脓毒症诱导的早期肺损伤中作为一种内在抗炎信号的重要作用，它调节了早期单核细胞/巨噬细胞驱动的炎症。
Sepsis is a serious clinical condition which can cause life-threatening organ dysfunction, and has limited therapeutic options. The paradigm of limiting excessive inflammation and promoting anti-inflammatory responses is a simplified concept. Yet, the absence of intrinsic anti-inflammatory signaling at the early stage of an infection can lead to an exaggerated activation of immune cells, including monocytes and macrophages. There is emerging evidence that endogenous molecules control those mechanisms. Here we aimed to identify and describe the dynamic changes in monocyte and macrophage subsets and lung damage in CL57BL/6N mice undergoing blunt chest trauma with subsequent cecal ligation and puncture. We showed that early an increase in systemic and activated Ly6C(+)CD11b(+)CD45(+)Ly6G(-) monocytes was paralleled by their increased emigration into lungs. The ratio of pro-inflammatory Ly6C(high)CD11b(+)CD45(+)Ly6G(-) to patrolling Ly6C(low)CD11b(+)CD45(+)Ly6G(-) monocytes significantly increased in blood, lungs and bronchoalveolar lavage fluid (BALF) suggesting an early transition to inflammatory phenotypes during early sepsis development. Similar to monocytes, the level of pro-inflammatory Ly6C(high)CD45(+)F4/80(+) macrophages increased in lungs and BALF, while tissue repairing Ly6C(low)CD45(+)F4/80(+) macrophages declined in BALF. Levels of inflammatory mediators TNF-alpha and MCP-1 in blood and RAGE in lungs and BALF were elevated, and besides their boosting of inflammation via the recruitment of cells, they may promote monocyte and macrophage polarization, respectively, toward the pro-inflammatory phenotype. Neutralization of uteroglobin increased pro-inflammatory cytokine levels, activation of inflammatory phenotypes and their recruitment to lungs; concurrent with increased pulmonary damage in septic mice. In in vitro experiments, the influence of uteroglobin on monocyte functions including migratory behavior, TGF-beta 1 expression, cytotoxicity and viability were proven. These results highlight an important role of endogenous uteroglobin as intrinsic anti-inflammatory signal upon sepsis-induced early lung injury, which modules the early monocyte/macrophages driven inflammation.SHORT SUMMARYBlunt chest injury is the third largest cause of death following major trauma, and ongoing excessive pro-inflammatory immune response entails high risk for the development of secondary complications, such as sepsis, with limited therapeutic options. In murine double hit trauma consisting of thoracic trauma and subsequent cecal ligation and puncture, we investigated the cytokine profile, pulmonary epithelial integrity and phenotypic shift of patrolling Ly6C(low)CD11b(+)CD45(+)Ly6G(-) monocytes and Ly6C(low)CD45(+)F4/80(+) macrophages to pro-inflammatory Ly6C(high)CD11b(+)CD45(+)Ly6G(-) monocytes and Ly6C(high)CD45(+)F4/80(+) cells in blood, lungs and bronchoalveolar lavage fluid (BALF). Pro-inflammatory mediators and phenotypes were elevated and uteroglobin neutralization led to further increase. Enhanced total protein levels in BALF suggests leakage of respiratory epithelium. In vitro, uteroglobin inhibited the migratory capacity of monocytes and the TGF-beta 1 expression without affecting the viability. These results highlight an important role of endogenous uteroglobin as an intrinsic anti-inflammatory signal upon sepsis-induced early lung injury, which modulates the early monocyte/macrophages driven inflammation.