Li Weijue, Zhu Haoyang, Zou Xiaoyu, Ye Hui, Zhong Jia, Xiang Shasha, Lou Yi, Mao Jiali, Qi Lingyun, Hu Xiawei, Zhang Yan, Hou Jinchao, Wang Bingduo, Bode Christian, Hoeft Andreas, Li Xuekun, Zhang Kai, Colonna Marco, Fang Xiangming
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China.
Immunity. 2025 Aug 12;58(8):2069-2085.e9. doi: 10.1016/j.immuni.2025.05.005. Epub 2025 Jun 3.
Severe pneumonia is predominantly caused by cytokine storms in the lung, but whether this process is controlled by the brain-lung axis remains unclear. Here, we found that GABAergic neurons in the central amygdala (CeA) were highly activated during severe pneumonia, which substantially contributed to inflammation and lung injury. Inhibition of CeA GABAergic neurons mitigated cytokine storms and improved survival rates in lethal pneumonia in mice. We uncovered a CeA-rostral ventrolateral medulla-sympathetic neural pathway connecting the brain to the lung, which enhanced norepinephrine (NE) release and amplified inflammatory signals. A subpopulation of β2-adrenergic receptor (ADRB2) interstitial macrophages surrounding the pulmonary sympathetic nerves (PSNs) responded to elevated NE, which aggravated inflammation and lung injury during severe pneumonia. Specific inhibition of PSNs and ADRB2 signaling improved the outcomes of severe pneumonia. Our study identifies a crucial brain-to-lung sympathetic signal controlling macrophage-mediated lung inflammatory responses, which could be harnessed as a therapeutic strategy for severe pneumonia.
重症肺炎主要由肺部的细胞因子风暴引起，但这一过程是否受脑-肺轴控制仍不清楚。在这里，我们发现，在重症肺炎期间，中央杏仁核（CeA）中的γ-氨基丁酸能神经元被高度激活，这在很大程度上导致了炎症和肺损伤。抑制CeAγ-氨基丁酸能神经元可减轻细胞因子风暴，并提高小鼠致死性肺炎的存活率。我们发现了一条连接大脑与肺部的CeA-延髓头端腹外侧区-交感神经通路，该通路增强了去甲肾上腺素（NE）的释放并放大了炎症信号。围绕肺交感神经（PSN）的β2-肾上腺素能受体（ADRB2）间质巨噬细胞亚群对升高的NE作出反应，这在重症肺炎期间加重了炎症和肺损伤。特异性抑制PSN和ADRB2信号改善了重症肺炎的预后。我们的研究确定了一种控制巨噬细胞介导的肺部炎症反应的关键脑-肺交感神经信号，这可作为重症肺炎的一种治疗策略。
