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

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.