Monocyte-derived macrophages are key players in tissue homeostasis and diseases regulated by a variety of signaling molecules. Recent literature has highlighted the ability for biogenic amines to regulate macrophage functions, but the mechanisms governing biogenic amine signaling in and around immune cells remains nebulous. In the central nervous system (CNS), biogenic amine transporters are regarded as the master regulators of neurotransmitter signaling. While we and others have shown that macrophages express these transporters, relatively little is known of their function in these cells. To address these knowledge gaps, we investigated the function of norepinephrine (NET) and dopamine (DAT) transporters on human monocyte-derived macrophages. We found that both NET and DAT are present and can uptake substrate from the extracellular space at baseline. Not only was DAT expressed in cultured monocyte-derived macrophages (MDMs), but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immuno-modulatory mechanism in response to lipopolysaccharide (LPS). LPS induced reverse transport of dopamine through DAT, engaging an autocrine/paracrine signaling loop that regulated the macrophage response. Removing this signaling loop enhanced the pro-inflammatory response to LPS. Collectively, our data introduce a potential role for DAT in the regulation of innate immunity.

No abstract

Neuromodulators, such as norepinephrine and dopamine, regulate immune responses. In addition to receptor competency, select immune cells express machinery to engage in active neurotransmitter transmission. Specifically, macrophages express the norepinephrine (NET) and dopamine transporters (DAT). However, how these transporters ‐ classically studied in central neurons ‐ affect immunity remains poorly understood. To this end, we investigated the expression and function of NET and DAT in human macrophages. We found that monocyte‐derived macrophages express functional NET and DAT in vitro. A subset of human intestinal macrophages were further confirmed to express DAT in situ. Interestingly, we discovered that inhibiting DAT, but not NET, enhanced the pro‐inflammatory macrophage program in response to an immune challenge. We attribute this modulation to an observed LPS‐induced efflux of dopamine through DAT that engages an autocrine dopamine signaling loop. Collectively, we propose that DAT actively regulates dopamine signaling on immune cells, and, in this context, DAT on macrophages is a novel, dynamic immunomodulator.

Monocyte-derived macrophages are key players in tissue homeostasis and disease regulated by a variety of signaling molecules. Recent literature has highlighted the ability for biogenic amines to regulate macrophage functions, but the mechanisms governing biogenic amine signaling on and around immune cells remains nebulous. In the central nervous system, biogenic amine transporters are regarded as the master regulators of neurotransmitter signaling. While we and others have shown macrophages express these transporters, relatively little is known of their function on these cells. To address these knowledge gaps, we interrogated the function of norepinephrine (NET) and dopamine (DAT) transporters on human monocyte-derived macrophages. We found that both NET and DAT are present and can uptake substrate from the extracellular space at baseline. Not only was DAT expressed in cultured macrophages, but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immuno-modulatory mechanism in response to lipopolysaccharide (LPS). LPS induced reverse transport of dopamine through DAT, engaging autocrine/paracrine signaling loop that regulated the macrophage response. Removing this signaling loop enhanced the pro-inflammatory response to LPS. Finally, we found that this DAT-immune axis was disrupted in disease. Collectively, our data introduce a novel role for DAT in the regulation of innate immunity during health and disease.