Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner

Abstract

SUMMARYThe innate immune system is the frontline of host defense against microbial infections, but its rapid and uncontrolled activation elicits microbicidal mechanisms that have deleterious effects [1,2]. Increasing evidence indicates that the metazoan nervous system, which responds to stimuli originating from both the internal and the external environment, functions as a modulatory apparatus that controls not only microbial killing pathways but also cellular homeostatic mechanisms [3][4][5]. Here, we report that dopamine signaling controls innate immune responses through a D1-like dopamine receptor, DOP-4, in Caenorhabditis elegans. Chlorpromazine inhibition of DOP-4 in the nervous system activates a microbicidal PMK-1/p38 mitogen-activated protein kinase signaling pathway that enhances host resistance against bacterial infections. The immune inhibitory function of dopamine originates in CEP neurons and requires active DOP-4 in downstream ASG neurons. Our findings indicate that dopamine signaling from the nervous system controls immunity in a cell non-autonomous manner and identifies the dopaminergic system as a potential therapeutic target for not only infectious diseases but also a range of conditions that arise as a consequence of malfunctioning immune responses. RESULTS AND DISCUSSIONThe ability of an organism to survive microbial infections requires tightly controlled activation of immune responses. Excessive inflammation can lead to conditions such as Crohn's disease, rheumatoid arthritis, Alzheimer's disease, and many other diseases that involve aberrant inflammation. Indeed, to survive an infection and return to homeostasis, animals appear to rely on reflex circuits that prevent inflammation when triggered by bacterial products or inflammatory cues [6,7]. This rapid and precise communication between the nervous and immune systems serves as an ancestral mechanism to control immune homeostasis in metazoans. * Correspondence: a.aballay@duke.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AUTHOR CONTRIBUTIONSX.C. and A.A. conceived and designed experiments. X.C. performed experiments. X.C. and A.A. analyzed the data and wrote the paper. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptIncreasing evidence highlights the importance of the vagus nerve circuit in the mediation of anti-inflammatory effects [8]. Recent studies have demonstrated that electroacupuncture requires intact sciatic and vagus nerves to inhibit inflammation by promoting the release of dopamine in the adrenal medulla [9,10]. Dopamine is a well-characteri...

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