Local immunity of the lung needs to be under tight control. However, how efferent neural signals influence lung immunity remains incompletely understood. Here, we report the development of a modified iDISCO-based protocol, iDISCO(ace), for whole-tissue 3D assessment of neural innervations and immune reactions in intact, unsectioned lung tissues. We observed that genetic, pharmacologic, or surgical removal of local sympathetic innervations promoted LPS-elicited innate immune response in the lung. Also, sympathetic ablation enhanced IL-33–elicited type 2 innate immunity. We further show that the sympathetic neurotransmitter norepinephrine, or specific agonists of the β2-adrenergic receptor, can inhibit the LPS- or IL-33–elicited immune response in a cell-intrinsic manner. Moreover, genetic deletion of the β2-adrenergic receptor produced immunomodulatory effects similar to those observed with sympathetic ablation. Together, this study elucidates the critical function of local sympathetic innervations in negatively modulating the lung innate immune responses.

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