Resolvin D1 Polarizes Primary Human Macrophages toward a Proresolution Phenotype through GPR32

Abstract

Resolvin D1 (RvD1) was shown to be a potent anti-inflammatory and proresolution lipid mediator in several animal models of inflammation, but its mechanism of action in humans is not clear. We show that the RvD1 receptor GPR32 is present on resting, proinflammatory M(LPS) and alternatively activated primary human M(IL-4) macrophages, whereas TGF-β and IL-6 reduce its membrane expression. Accordingly, stimulation of resting primary human macrophages with 10 nM RvD1 for 48 h maximally reduced the secretion of the proinflammatory cytokines IL-1β and IL-8; abolished chemotaxis to several chemoattractants like chemerin, fMLF, and MCP-1; and doubled the phagocytic activity of these macrophages toward microbial particles. In contrast, these functional changes were not accompanied by surface expression of markers specific for alternatively activated M(IL-4) macrophages. Similar proresolution effects of RvD1 were observed when proinflammatory M(LPS) macrophages were treated with RvD1. In addition, we show that these RvD1-mediated effects are GPR32 dependent because reduction of GPR32 expression by small interfering RNA, TGF-β, and IL-6 treatment ablated these proresolution effects in primary human macrophages. Taken together, our results indicate that in humans RvD1 triggers GPR32 to polarize and repolarize macrophages toward a proresolution phenotype, supporting the role of this mediator in the resolution of inflammation in humans.

Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology

“…For instance, it was recently shown that RvD1 blunts macrophage chemotaxis toward CCL2, while enhancing phagocytic function. In human macrophages, RvD1 potently blocks production of pro-inflammatory cytokines (e.g., IL-1β, IL-8 and CCL2) in a GPR32-dependent manner, which could help to prevent further recruitment of inflammatory monocytes 142 . In inflamed obese adipose tissue, RvD1 decreases the proportion of inflammatory macrophages and enhances macrophage phagocytosis and expression of arginase 1 143, 144 .…”

Pro-Resolving Molecules—New Approaches to Treat Sepsis?

“…RvD1 effects on macrophages seem to be transmitted by G protein-coupled receptor 32(GPR32) and the FPR2/ALX receptor [84,92,93]. …”

Prevention of Chronic Post-Thoracotomy Pain in Rats By Intrathecal Resolvin D1 and D2: Effectiveness of Perioperative and Delayed Drug Delivery

“…29,37,38,47,49,51 Resolvins have direct actions on the recruitment and migration of neutrophils and macrophages, underlying the resolution phase of inflammation 48,51–53 , and they also alter peripheral and central nervous system responses to inflammation and injury, through direct actions on neurons and glia. 65 Since the drugs that are traditionally used to treat inflammatory and post-operative pain, namely opiates and cyclo-oxygenase-2 (COX-2) inhibitors, have unwanted side effects, there is a need to find new approaches and compounds that will be more selective in their actions and have fewer adverse actions.…”

“…The primary target is one of the GPCRs known to bind resolvins; for RvD1 the receptor in rodents is ALX/FPR2 11,15,42,48 and for RvD2 the receptor is GPR18. 10 In macrophages RvD2 activation of GPR18 stimulates intracellular increases in cAMP without increasing intracellular Ca 2+ while RvD1 activation of ALX/FPR2 stimulates phosphorylation rather than increase in intracellular Ca 2+ or cAMP.…”