A brain-to-lung signal from GABAergic neurons to ADRB2+ interstitial macrophages promotes pulmonary inflammatory responses

Weijue Li; Haoyang Zhu; Xiaoyu Zou; Hui Ye; Jia Zhong; Shasha Xiang; Yi Lou; Jiali Mao; Lingyun Qi; Xiawei Hu; Yan Zhang; Jinchao Hou; Bingduo Wang; Christian Bode; Andreas Hoeft; Xuekun Li; Kai Zhang; Marco Colonna; Xiangming Fang

doi:10.1016/j.immuni.2025.05.005

A brain-to-lung signal from GABAergic neurons to ADRB2⁺ interstitial macrophages promotes pulmonary inflammatory responses

Immunity. 2025 May 28:S1074-7613(25)00226-2. doi: 10.1016/j.immuni.2025.05.005. Online ahead of print.

Authors

Weijue Li¹, Haoyang Zhu¹, Xiaoyu Zou², Hui Ye², Jia Zhong¹, Shasha Xiang¹, Yi Lou¹, Jiali Mao¹, Lingyun Qi¹, Xiawei Hu¹, Yan Zhang², Jinchao Hou³, Bingduo Wang⁴, Christian Bode⁵, Andreas Hoeft⁵, Xuekun Li⁶, Kai Zhang⁷, Marco Colonna⁸, Xiangming Fang⁹

Affiliations

¹ Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China.
³ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
⁵ Department of Anesthesiology and Intensive Care Medicine, University Hospital of Bonn, Bonn, Germany.
⁶ The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Binjiang Institute of Zhejiang University, Hangzhou, China.
⁷ Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: kai_zhang@zju.edu.cn.
⁸ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mcolonna@pathology.wustl.edu.
⁹ Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: xmfang@zju.edu.cn.

PMID: 40466637
DOI: 10.1016/j.immuni.2025.05.005

Abstract

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.

Keywords: GABAergic neuron; central amygdala; inflammation; macrophage; norepinephrine; pneumonia; pulmonary sympathetic nerve; β2-adrenergic receptor.