前列腺素E2的代谢调节损害肺2组固有淋巴样细胞反应
2022/11/22
摘要
背景：第2组先天淋巴样细胞(ILC2s)在哮喘发病中起着关键作用。非甾体抗炎药(NSAID)-加重性呼吸道疾病(NERD)与前列腺素E2 (PGE2)受体EP2信号减弱有关。然而，PGE2受体EP2和EP4(两者共享相同的下游信号)在调节肺ILC2反应中的各自作用尚未被破译。
方法：在IL-33诱导的肺过敏模型中，利用转基因小鼠系和药理学方法研究了PGE2受体EP2和EP4在ILC2介导的肺炎症中的作用。通过体外细胞培养检测了PGE2受体及其下游信号对ILC2代谢激活和效应功能的影响。
结果：EP2而不是EP4的缺乏增强了IL-33诱导的小鼠肺ILC2反应和体内嗜酸性粒细胞炎症。相反，EP4和EP2的外源性激动作用或磷酸二酯酶的抑制作用显著抑制IL-33诱导的肺ILC2反应。机制上，PGE2通过EP2/EP4-cAMP通路直接抑制IL-33依赖的ILC2激活，从而下调STAT5和MYC通路基因表达和ILC2能量代谢。在内源性PG合成或EP2信号被阻断的小鼠中，阻断糖酵解可以减少il -33依赖的ILC2反应，但在PGE2-EP2信号完整的小鼠中则没有。
结论：我们已经确定了一种通过内源性PGE2-EP2信号抑制小鼠肺ILC2反应的最佳机制，这支持了NERD患者中EP2信号缺陷的临床发现。我们的研究结果还表明，外源靶向PGE2-EP4-cAMP和能量代谢通路可能为治疗哮喘和NERD中ILC2引发的肺部炎症提供了新的机会。
Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses
C. T. Robb, Y. Zhou, J. M. Felton, B. R. Zhang, M. Goepp, P. Jheeta, et al.
Abstract
BACKGROUND：Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered.
METHODS：The roles of PGE2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures.
RESULTS：Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE2-EP2 signaling.
CONCLUSIONS：We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE2-EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2-EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating the ILC2-initiated lung inflammation in asthma and NERD.
背景：第2组先天淋巴样细胞(ILC2s)在哮喘发病中起着关键作用。非甾体抗炎药(NSAID)-加重性呼吸道疾病(NERD)与前列腺素E2 (PGE2)受体EP2信号减弱有关。然而，PGE2受体EP2和EP4(两者共享相同的下游信号)在调节肺ILC2反应中的各自作用尚未被破译。
方法：在IL-33诱导的肺过敏模型中，利用转基因小鼠系和药理学方法研究了PGE2受体EP2和EP4在ILC2介导的肺炎症中的作用。通过体外细胞培养检测了PGE2受体及其下游信号对ILC2代谢激活和效应功能的影响。
结果：EP2而不是EP4的缺乏增强了IL-33诱导的小鼠肺ILC2反应和体内嗜酸性粒细胞炎症。相反，EP4和EP2的外源性激动作用或磷酸二酯酶的抑制作用显著抑制IL-33诱导的肺ILC2反应。机制上，PGE2通过EP2/EP4-cAMP通路直接抑制IL-33依赖的ILC2激活，从而下调STAT5和MYC通路基因表达和ILC2能量代谢。在内源性PG合成或EP2信号被阻断的小鼠中，阻断糖酵解可以减少il -33依赖的ILC2反应，但在PGE2-EP2信号完整的小鼠中则没有。
结论：我们已经确定了一种通过内源性PGE2-EP2信号抑制小鼠肺ILC2反应的最佳机制，这支持了NERD患者中EP2信号缺陷的临床发现。我们的研究结果还表明，外源靶向PGE2-EP4-cAMP和能量代谢通路可能为治疗哮喘和NERD中ILC2引发的肺部炎症提供了新的机会。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Allergy, 2022 ;00:1–17 DOI: 10.1111/all.15541）
（Allergy, 2022 ;00:1–17 DOI: 10.1111/all.15541）
Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses
C. T. Robb, Y. Zhou, J. M. Felton, B. R. Zhang, M. Goepp, P. Jheeta, et al.
Abstract
BACKGROUND：Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered.
METHODS：The roles of PGE2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures.
RESULTS：Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE2-EP2 signaling.
CONCLUSIONS：We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE2-EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2-EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating the ILC2-initiated lung inflammation in asthma and NERD.
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重症哮喘患者呼吸道感染自身抗体介导的巨噬细胞功能障碍
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过敏性哮喘加重中的气道纤维蛋白形成级联:炎症和重塑的意义
