Where Is Dopamine and how do Immune Cells See it?: Dopamine-Mediated Immune Cell Function in Health and Disease.

Dopamine is well recognized as a neurotransmitter in the brain, and regulates critical functions in a variety of peripheral systems. Growing research has also shown that dopamine acts as an important regulator of immune function. Many immune cells express dopamine receptors and other dopamine related proteins, enabling them to actively respond to dopamine and suggesting that dopaminergic immunoregulation is an important part of proper immune function. A detailed understanding of the physiological concentrations of dopamine in specific regions of the human body, particularly in peripheral systems, is critical to the development of hypotheses and experiments examining the effects of physiologically relevant dopamine concentrations on immune cells. Unfortunately, the dopamine concentrations to which these immune cells would be exposed in different anatomical regions are not clear. To address this issue, this comprehensive review details the current information regarding concentrations of dopamine found in both the central nervous system and in many regions of the periphery. In addition, we discuss the immune cells present in each region, and how these could interact with dopamine in each compartment described. Finally, the review briefly addresses how changes in these dopamine concentrations could influence immune cell dysfunction in several disease states including Parkinson's disease, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, as well as the collection of pathologies, cognitive and motor symptoms associated with HIV infection in the central nervous system, known as NeuroHIV. These data will improve our understanding of the interactions between the dopaminergic and immune systems during both homeostatic function and in disease, clarify the effects of existing dopaminergic drugs and promote the creation of new therapeutic strategies based on manipulating immune function through dopaminergic signaling. Graphical Abstract.

Dopamine activates NF-κB and primes the NLRP3 inflammasome in primary human macrophages.

Induction of innate immune genes in the brain is thought to be a major factor in the development of addiction to substances of abuse. As the major component of the innate immune system in the brain, aberrant activation of myeloid cells such as macrophages and microglia due to substance use may mediate neuroinflammation and contribute to the development of addiction. All addictive drugs modulate the dopaminergic system and our previous studies have identified dopamine as a pro-inflammatory modulator of macrophage function. However, the mechanism that mediates this effect is currently unknown. Inflammatory activation of macrophages and induction of cytokine production is often mediated by the transcription factor NF-κB, and prior studies have shown that dopamine can modulate NF-κB activity in T-cells and other non-immune cell lines. Here we demonstrated that dopamine can activate NF-κB in primary human macrophages, resulting in the induction of its downstream targets including the NLRP3 inflammasome and the inflammatory cytokine IL-1ß. These data also indicate that dopamine primes but does not activate the NLRP3 inflammasome in human macrophages. Activation of NF-κB was required for dopamine-mediated increases in IL-1ß, as an inhibitor of NF-κB was able to abrogate the effects of dopamine on production of these cytokines. Connecting an increase in extracellular dopamine to NF-κB activation and inflammation suggests specific intracellular targets that could be used to ameliorate the inflammatory impact of dopamine in neuroinflammatory conditions associated with myeloid cell activation such as addiction.

Dopamine increases HIV entry into macrophages by increasing calcium release via an alternative signaling pathway.

Dopaminergic dysfunction has long been connected to the development of HIV infection in the CNS. Our previous data showed that dopamine increases HIV infection in human macrophages by increasing the susceptibility of primary human macrophages to HIV entry through stimulation of both D1-like and D2-like receptors. These data suggest that, in macrophages, both dopamine receptor subtypes may act through a common signaling mechanism. To define better the mechanism(s) underlying this effect, this study examines the specific signaling processes activated by dopamine in primary human monocyte-derived macrophages (hMDM). In addition to confirming that the increase in entry is unique to dopamine, these studies show that dopamine increases HIV entry through a PKA insensitive, Ca2+ dependent pathway. Further examination demonstrated that dopamine can signal through a previously defined, non-canonical pathway in human macrophages. This pathway involves both Ca2+ release and PKC phosphorylation, and these data show that dopamine mediates both of these effects and that both were partially inhibited by the Gq/11 specific inhibitor YM-254890. Studies have shown that Gq/11 preferentially couples to the D1-like receptor D5, indicating an important role of the D1-like receptors in mediating these effects. These data indicate a role for Ca2+ flux in the HIV entry process, and suggest a distinct signaling mechanism mediating some of the effects of dopamine in macrophages. Together, the data indicate that targeting this alternative dopamine signaling pathway might provide new therapeutic options for individuals with elevated CNS dopamine suffering from NeuroHIV.