Abstract
Neurotransmitters have been shown to regulate immune responses, and thereby are critically related to autoimmune diseases. Here we showed that depletion of dopaminergic neurons significantly promoted activation of hepatic iNKT cells and augmented concanavalin A (Con A)-induced liver injury. The suppressive effect of dopamine on iNKT cells was mediated by D1-like receptor-PKA pathway. Clearance of gut microbiota by antibiotic cocktail reduced synthesis of dopamine in intestines and exacerbated liver damage, and that could be restored by recovery of gut microbiota or replenishment of D1-like receptor agonist. Our results demonstrate that peripheral dopamine controlled by gut microbes inhibits IL4 and IFNγ production in iNKT cells and suppresses iNKT cell-mediated hepatitis. Together, we propose a gut microbe-nervous system-immune system regulatory axis in modulating autoimmune hepatitis.
Highlights
Recent studies indicate a crosstalk between nervous system and immune system
It has been reported that activation of D1-like receptors inhibits suppressive functions of regulatory T cells, and promotes differentiation of T helper 2 (Th2) and especially T helper 17 (Th17) in naïve CD4+ T cells [31]
Dopamine released by dendritic cells increases their IL12 and IL23 production through DRD5 in an autocrine manner, and promotes Th17 differentiation [32], which contributes to inflammatory bowel diseases and multiple sclerosis
Summary
Recent studies indicate a crosstalk between nervous system and immune system. Neurotransmitters, neuropeptides, cytokines and their receptors are main mediators in the neuro-immune network. D1-like dopamine receptors (DRD) including DRD1 and DRD5 activate adenylyl cyclase, whereas D2-like receptors including DRD2, DRD3, and DRD4 inhibit adenylyl cyclase. These receptors show distinct affinity for dopamine: DRD3 > DRD5 > DRD4 > DRD2 > DRD1 [5]. Dopamine displays complex regulatory effect on immune responses, depending on dopamine concentration, subtype of receptors and type of immune cells. As an important immune regulator, peripheral dopamine is mainly produced by autonomic nervous system, gut epithelial cells, and immune cells including dendritic cells, regulatory T cells, B cells, and macrophages [5]. About 50% dopamine is produced in gastrointestinal tract by enteric neurons and intestinal epithelial
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