Local sympathetic innervations modulate the lung innate immune responses

Area of Science:

• Immunology
• Neuroscience
• Pulmonology

Background:

• Lung immunity requires precise regulation.
• The influence of efferent neural signals on lung immunity is not fully understood.

Purpose of the Study:

• To investigate the role of sympathetic innervation in modulating lung innate immune responses.
• To develop a novel method for 3D assessment of neural and immune interactions in intact lung tissue.

Main Methods:

• Development of a modified iDISCO protocol (iDISCO(ace)) for whole-tissue 3D imaging.
• Assessment of immune responses following sympathetic denervation (genetic, pharmacologic, surgical) in mouse models.
• Evaluation of the effects of norepinephrine and beta2-adrenergic receptor agonists/antagonists.

Main Results:

• Sympathetic denervation enhanced lipopolysaccharide (LPS)-induced innate immunity and IL-33-induced type 2 innate immunity in the lung.
• Norepinephrine and beta2-adrenergic receptor agonists inhibited LPS- and IL-33-elicited immune responses in a cell-intrinsic manner.
• Genetic deletion of the beta2-adrenergic receptor mimicked the effects of sympathetic denervation.

Conclusions:

• Local sympathetic innervation plays a critical role in negatively modulating lung innate immune responses.
• The beta2-adrenergic receptor pathway is a key mechanism by which sympathetic nerves regulate lung immunity.