2型先天性淋巴细胞中mTORC1信号传导协调过敏性肺部炎症中的神经 - 免疫串扰
2025/12/30
摘要
2型先天性淋巴细胞（ILC2）在过敏性哮喘中响应多种组织来源的刺激引发2型病理性炎症。然而，ILC2细胞整合并响应环境信号的分子机制尚不清楚。在这里，我们在小鼠模型中发现，在过敏性哮喘中，肺部ILC2细胞中雷帕霉素靶蛋白复合物1（mTORC1）的激活增加。基因敲除Raptor（mTORC1复合物的必需成分）会导致ILC2细胞中IL - 5和IL - 13的产生减少，并保护小鼠免受过敏性炎症的影响。雷帕霉素对mTORC1的药理学抑制可抑制ILC2的激活并改善过敏性肺部炎症。从机制上讲，mTORC1的激活通过表观遗传重编程上调神经调节素U受体1（NMUR1）的表达，从而增强ILC2对神经调节素U（NMU）的激活反应。然而，我们的实验表明，NMUR1并不是mTORC1下游ILC2激活的唯一介质。总之，我们的研究揭示了在ILC2中，mTORC1信号传导协调神经 - 免疫串扰以实现最佳激活，并强调mTORC1是过敏性哮喘的一个潜在治疗靶点。
mTORC1 signaling in group 2 innate lymphoid cells coordinates neuro-immune crosstalk in allergic lung inflammation
Dongdi Wang, Lin Hu, Jinyu Chen, Jinxin Qiu, Yue Chen, Michelle Zhang, Linfeng Zhao, Xiaohui Su, Jiping Sun, Ju Qiu, Wei Tang, Wenyong Zhou, Lei Shen
Abstract
Group 2 innate lymphoid cells (ILC2) initiate pathologic type 2 inflammation in allergic asthma in response to diverse tissue-derived stimuli. However, the molecular mechanisms by which ILC2 cells integrate and respond to environmental signals are unclear. Here, we show in a mouse model that in allergic asthma, mechanistic target of rapamycin complex 1 (mTORC1) activation in lung ILC2 cells increases. Genetic ablation of Raptor, an obligatory component of mTORC1 complex, results in reduced IL-5 and IL-13 production in ILC2 cells and protects mice from allergic inflammation. Pharmacological inhibition of mTORC1 by rapamycin suppresses ILC2 activation and ameliorates allergic lung inflammation. Mechanistically, mTORC1 activation upregulates neuromedin U receptor 1 (NMUR1) expression through epigenetic reprogramming, which augments ILC2 activation in response to neuromedin U (NMU). However, our experiments suggest that NMUR1 is not an exclusive mediator of ILC2 activation downstream of mTORC1. In conclusion, our work reveals that in ILC2s, mTORC1 signaling coordinates neuro-immune crosstalk for optimal activation, and highlights mTORC1 as a potential therapeutic target for allergic asthma.
2型先天性淋巴细胞（ILC2）在过敏性哮喘中响应多种组织来源的刺激引发2型病理性炎症。然而，ILC2细胞整合并响应环境信号的分子机制尚不清楚。在这里，我们在小鼠模型中发现，在过敏性哮喘中，肺部ILC2细胞中雷帕霉素靶蛋白复合物1（mTORC1）的激活增加。基因敲除Raptor（mTORC1复合物的必需成分）会导致ILC2细胞中IL - 5和IL - 13的产生减少，并保护小鼠免受过敏性炎症的影响。雷帕霉素对mTORC1的药理学抑制可抑制ILC2的激活并改善过敏性肺部炎症。从机制上讲，mTORC1的激活通过表观遗传重编程上调神经调节素U受体1（NMUR1）的表达，从而增强ILC2对神经调节素U（NMU）的激活反应。然而，我们的实验表明，NMUR1并不是mTORC1下游ILC2激活的唯一介质。总之，我们的研究揭示了在ILC2中，mTORC1信号传导协调神经 - 免疫串扰以实现最佳激活，并强调mTORC1是过敏性哮喘的一个潜在治疗靶点。
（中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校）
（Nat Commun. 2025 Nov 29. doi: 10.1038/s41467-025-66683-y.）
（Nat Commun. 2025 Nov 29. doi: 10.1038/s41467-025-66683-y.）
mTORC1 signaling in group 2 innate lymphoid cells coordinates neuro-immune crosstalk in allergic lung inflammation
Dongdi Wang, Lin Hu, Jinyu Chen, Jinxin Qiu, Yue Chen, Michelle Zhang, Linfeng Zhao, Xiaohui Su, Jiping Sun, Ju Qiu, Wei Tang, Wenyong Zhou, Lei Shen
Abstract
Group 2 innate lymphoid cells (ILC2) initiate pathologic type 2 inflammation in allergic asthma in response to diverse tissue-derived stimuli. However, the molecular mechanisms by which ILC2 cells integrate and respond to environmental signals are unclear. Here, we show in a mouse model that in allergic asthma, mechanistic target of rapamycin complex 1 (mTORC1) activation in lung ILC2 cells increases. Genetic ablation of Raptor, an obligatory component of mTORC1 complex, results in reduced IL-5 and IL-13 production in ILC2 cells and protects mice from allergic inflammation. Pharmacological inhibition of mTORC1 by rapamycin suppresses ILC2 activation and ameliorates allergic lung inflammation. Mechanistically, mTORC1 activation upregulates neuromedin U receptor 1 (NMUR1) expression through epigenetic reprogramming, which augments ILC2 activation in response to neuromedin U (NMU). However, our experiments suggest that NMUR1 is not an exclusive mediator of ILC2 activation downstream of mTORC1. In conclusion, our work reveals that in ILC2s, mTORC1 signaling coordinates neuro-immune crosstalk for optimal activation, and highlights mTORC1 as a potential therapeutic target for allergic asthma.
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