The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. In addition, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease. Despite the increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. To address this issue, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases including Parkinson9s disease, several neuropsychiatric conditions, neuroHIV, inflammatory bowel disease, psoriasis, rheumatoid arthritis, and sepsis. Careful consideration is given to the influence of experimental design on results, and we note several areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue and disease level and prompts the development of therapeutics and strategies targeted towards ameliorating disease through dopaminergic regulation of immunity. Significance Statement Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.

HIV infected people are living longer due to the success of combined antiretroviral therapy (cART). However, greater than 40-70% of HIV infected individuals develop HIV associated neurocognitive disorders (HAND) that continues to be a major public health issue. While cART reduces peripheral virus, it does not limit the low level, chronic neuroinflammation that is ongoing during the neuropathogenesis of HIV. Monocyte transmigration across the blood brain barrier (BBB), specifically that of the mature CD14⁺CD16⁺ population that is highly susceptible to HIV infection, is critical to the establishment of HAND as these cells bring virus into the brain and mediate the neuroinflammation that persists, even if at low levels, despite antiretroviral therapy. CD14⁺CD16⁺ monocytes preferentially migrate into the CNS early during peripheral HIV infection in response to chemotactic signals, including those from CCL2 and CXCL12. Once within the brain, monocytes differentiate into macrophages and elaborate inflammatory mediators. Monocytes/macrophages constitute a viral reservoir within the CNS and these latently infected cells may perpetuate the neuropathogenesis of HIV. This review will discuss mechanisms that mediate transmigration of CD14⁺CD16⁺ monocytes across the BBB in the context of HIV infection, the contribution of these cells to the neuropathogenesis of HIV, and potential monocyte/macrophage biomarkers to identify HAND and monitor its progression.

As HIV infected individuals live longer, the prevalence of HIV associated neurocognitive disorders is increasing, despite successful antiretroviral therapy. CD14⁺CD16⁺ monocytes are critical to the neuropathogenesis of HIV as they promote viral seeding of the brain and establish neuroinflammation. The mechanisms by which HIV infected and uninfected monocytes cross the blood brain barrier and enter the central nervous system are not fully understood. We determined that HIV infection of CD14⁺CD16⁺ monocytes resulted in their highly increased transmigration across the blood brain barrier in response to CCL2 as compared to uninfected cells, which did not occur in the absence of the chemokine. This exuberant transmigration of HIV infected monocytes was due, at least in part, to increased CCR2 and significantly heightened sensitivity to CCL2. The entry of HIV infected and uninfected CD14⁺CD16⁺ monocytes into the brain was facilitated by significantly increased surface JAM-A, ALCAM, CD99, and PECAM-1, as compared to CD14⁺ cells that are CD16 negative. Upon HIV infection, there was an additional increase in surface JAM-A and ALCAM on CD14⁺CD16⁺ monocytes isolated from some individuals. Antibodies to ALCAM and JAM-A inhibited the transmigration of both HIV infected and uninfected CD14⁺CD16⁺ monocytes across the BBB, demonstrating their importance in facilitating monocyte transmigration and entry into the brain parenchyma. Targeting CCR2, JAM-A, and ALCAM present on CD14⁺CD16⁺ monocytes that preferentially infiltrate the CNS represents a therapeutic strategy to reduce viral seeding of the brain as well as the ongoing neuroinflammation that occurs during HIV pathogenesis.