过敏性炎症反应中单核细胞和巨噬细胞分子昼夜节律时钟受损
2024/06/26
摘要
背景：支气管哮喘等炎症性疾病典型表现为强昼夜戒律，而巨噬细胞功能障碍为其常见特征。
方法：本研究监测了健康、过敏和哮喘受试者外周血单核细胞分子昼夜节律时钟相关蛋白质表达情况。通过培养上述单核细胞，本研究进一步检测了人类单核细胞衍生巨噬细胞、M1极化巨噬细胞和M2极化巨噬细胞的昼夜节律蛋白表达情况。
结果：在单核细胞中，特别是来自过敏性哮喘患者的单核细胞，昼夜节律蛋白CLOCK、BMAL、REV-ERBs和RORs的动态表达显著改变。在过敏受试者的极化巨噬细胞和活化精确切割肺切片中组织驻留巨噬细胞中，BMAL1也发生类似的变化。
通过减少巨噬细胞炎症蛋白的分泌和增强吞噬作用，本研究证实了ROR反向激动剂SR1001的时钟调节、抗炎和肺保护特性。通过屋尘螨模型，本研究在体内验证了SR1001的治疗效果。
结论：综上所述，本研究数据表明，在炎症性肺疾病中，分子昼夜节律时钟与单核细胞/巨噬细胞效应器功能之间存在相互作用。SR1001可导致体外和体内炎症消退，并游玩成为一种基于时钟的慢性肺部疾病（如哮喘）的治疗手段。
The disrupted molecular circadian clock of monocytes and macrophages in allergic inflammation.
Teppan J, Schwanzer J, Rittchen S, Bärnthaler T, Lindemann J, Nayak B, Reiter B, Luschnig P, Farzi A, Heinemann A, Sturm E.
Abstract
BACKGROUND:Macrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm.
OBJECTIVE:To decipher the functions of gasdermin B (encoded by GSDMB) in respiratory virus-induced lung inflammation.
METHODS:We monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocyte-derived macrophages, M1- and M2- polarized macrophages.
RESULTS:
In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo.
CONCLUSION: Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma.
背景：支气管哮喘等炎症性疾病典型表现为强昼夜戒律，而巨噬细胞功能障碍为其常见特征。
方法：本研究监测了健康、过敏和哮喘受试者外周血单核细胞分子昼夜节律时钟相关蛋白质表达情况。通过培养上述单核细胞，本研究进一步检测了人类单核细胞衍生巨噬细胞、M1极化巨噬细胞和M2极化巨噬细胞的昼夜节律蛋白表达情况。
结果：在单核细胞中，特别是来自过敏性哮喘患者的单核细胞，昼夜节律蛋白CLOCK、BMAL、REV-ERBs和RORs的动态表达显著改变。在过敏受试者的极化巨噬细胞和活化精确切割肺切片中组织驻留巨噬细胞中，BMAL1也发生类似的变化。
通过减少巨噬细胞炎症蛋白的分泌和增强吞噬作用，本研究证实了ROR反向激动剂SR1001的时钟调节、抗炎和肺保护特性。通过屋尘螨模型，本研究在体内验证了SR1001的治疗效果。
结论：综上所述，本研究数据表明，在炎症性肺疾病中，分子昼夜节律时钟与单核细胞/巨噬细胞效应器功能之间存在相互作用。SR1001可导致体外和体内炎症消退，并游玩成为一种基于时钟的慢性肺部疾病（如哮喘）的治疗手段。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Front Immunol. 2024 May 28;15:1408772. doi: 10.3389/fimmu.2024.1408772.)
(Front Immunol. 2024 May 28;15:1408772. doi: 10.3389/fimmu.2024.1408772.)
The disrupted molecular circadian clock of monocytes and macrophages in allergic inflammation.
Teppan J, Schwanzer J, Rittchen S, Bärnthaler T, Lindemann J, Nayak B, Reiter B, Luschnig P, Farzi A, Heinemann A, Sturm E.
Abstract
BACKGROUND:Macrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm.
OBJECTIVE:To decipher the functions of gasdermin B (encoded by GSDMB) in respiratory virus-induced lung inflammation.
METHODS:We monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocyte-derived macrophages, M1- and M2- polarized macrophages.
RESULTS:
In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo.
CONCLUSION: Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma.
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