Two distinct mechanisms have been described

Two distinct mechanisms have been described for niacin’s macrophage-based actions [21,22]. First, niacin blocks recruitment of macrophages to atherosclerotic lesions. Second, niacin upregulates macrophage ABCA1 and ABCG1, transporters involved in reverse cholesterol transport. Upregulation of cholesterol transporters ABCA1 and ABCG1 by niacin is mediated by GPR109A dependent elevation of cAMP, resulting from integration of signals from two distinct signaling cascades [11,20,22]. First, similar to Langerhans cells, treatment of macrophages with niacin leads to release of prostanoids PGE2 and PGD2 through activation of several GPR109A signaling pathways including calcium flux and Erk activation. Second, niacin acting through GPR109A releases Gi protein derived Gβγ to engage cAMP stimulatory machinery, instead of engaging classical Gi mediated cAMP inhibitory machinery through the Gαi subunit. This Giβγ and Gαs signal convergence is partially enabled by a specific milieu of macrophage expressed adenylyl cyclases, where the highest expressed isoform (AC7) is regulated both by Gs derived α subunits and Gi derived Gβγ subunits in a cooperative fashion [11]. Direct examination of the hypothesis that GPR84 may have similar antiatherosclerotic activities in macrophages revealed that GPR84 activation by embelin indeed leads to Gi and COX mediated PGE2 release, cAMP upregulation, elevation of expression of ABCA1 and ABCG1 cholesterol transporters, and stimulation of reverse cholesterol transport. While GPR84 shares these anti-atherosclerotic properties with GPR109A, we found no evidence that its activation inhibits migration to other inflammatory or chemotactic stimuli; GPR84 is rather by itself a chemotactic receptor. However, if inflammatory mediators serving as GPR84 agonists are involved in recruitment of macrophages to the sites of developing atherosclerotic plaques, then it is possible that systemic introduction of GPR84 agonists may disrupt endogenous agonist gradients and thus have beneficial anti-atherosclerotic effects on macrophage recruitment, in addition to their effect on cholesterol efflux. The potential absence of significant functional GPR84 in dermal Langerhans euk 134 suggests GPR84 agonists may not produce the flushing effects seen with GPR109A agonists. Thus, GPR84 may serve as a potentially attractive target for the development of anti-atherosclerotic agents.
Declaration of interest
Acknowledgment
Introduction Several G-protein coupled receptors act as sensors/receptors for fatty acids [1], [2]. GPR120 (or FFAR4), is a receptor for n-3 polyunsaturated fatty acids, and has been linked to the anti-inflammatory action of these lipids [2], [3]. The primary ligands for GPR41 (FFAR3) and GPR43 (FFAR2) are short chain fatty acids, while GPR40 (FFAR1) is activated by medium and long chain saturated and mono-unsaturated fatty acids [1], [2]. GPR84 (EX33), a pro-inflammatory receptor, is also activated by medium chain fatty acids [4], [5]. Each of these GPCRs has a distinct tissue distribution, with GPR120 being strongly expressed in both adipocytes and macrophages (M1 and M2) in white adipose tissue, where it promotes adipogenesis [6] in addition to insulin sensitising and anti-inflammatory actions [2], [3]. Adipocytes also express GPR84, and at least in the case of human fat cells GPR40, GPR41 and GPR43, albeit at low levels [7]. Recent studies have shown that the expression of GPR84, GPR41 and GPR120 is powerfully and differentially modulated by inflammatory mediators. Macrophage-conditioned medium, lipopolysaccharide, TNFα and IL-1β have each been shown to strongly stimulate GPR84 expression [4], [7], [8], [9]. In contrast, GPR120 expression is markedly reduced by these agents [7], [8]. IL-1β induces a particularly strong stimulation of GPR84 expression in human adipocytes and the expression of GPR41 is also increased [7]. The IL-1 superfamily of cytokines comprises other pro-inflammatory agonists in addition to IL-1β, including IL-18 and IL-33 [10], both of which are produced by human white adipocytes [10], [11]. However, the main source of IL-33 in human adipose tissue appears to be endothelial cells [12]. IL-33 has multiple effects in inflammation and immunity, involving the stimulation of regulatory T (T) cells and the production of Th2 cytokines and chemokines such as IL-5, IL-6 and MCP-1, including in adipose tissue [13].