Abstract
Monocyte-derived macrophages (MDMs) 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 remain nebulous. In the 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 transporter (NET) and dopamine transporter (DAT) on human MDMs. 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 MDMs, but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immunomodulatory mechanism in response to 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 proinflammatory response to LPS. Our data introduce a potential role for DAT in the regulation of innate immunity.
Highlights
Monocytes and monocyte-derived macrophages (MDMs) are heterogenous populations that serve as critical components of the immune system
Using a previously published protocol generated in our lab [23], we measured the percent of freshly isolated monocytes expressing either norepinephrine (NET) or dopamine (DAT) transporters
18% of monocytes were dopamine transporter (DAT)+; whereas approximately 4-5% of monocytes were norepinephrine transporter (NET)+ and no monocytes were positive for serotonin transporter (SERT, Figure 1B, gating strategy shown in Supplemental Figure 1)
Summary
Monocytes and monocyte-derived macrophages (MDMs) are heterogenous populations that serve as critical components of the immune system. Fundamental MDM functions include phagocytosis, cytokine production and antigen presentation, and defective or aberrant macrophage functions have been associated with inflammatory [4], autoimmune [5], and neurological diseases [6, 7]. Biogenic amines, such as norepinephrine, in particular have been noted for their ability to dynamically regulate macrophage function [8]. A subset of intestinal macrophages express betaadrenergic receptors that engage a tissue-protective phenotype [9], and adipose macrophages adjacent to sympathetic terminals express a functional norepinephrine transporter (NET) that modulates the pro-inflammatory state and thermogenesis [10], indicating that the biogenic amine transporter activity itself can influence the immune system
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