Uncovering the Power of GPR18 Signalling: How RvD2 and Other Ligands Could Have the Potential to Modulate and Resolve Inflammation in Various Health Disorders

Abstract

The resolution of inflammation is the primary domain of specialised pro-resolving mediators (SPMs), which include resolvins, protectins, and their forms synthesised under the influence of aspirin and the maresins. The role of these SPMs has been discussed by many authors in the literature, with particular reference to neuroinflammation and significant neurological disorders. This review discusses the role of G protein-coupled receptor 18 (GPR18), resolvin D2 (RvD2) activity, and the GPR18-RvD2 signalling axis, as well as the role of small molecule ligands of GPR18 in inflammation in various health disorders (brain injuries, neuropathic pain, neurodegenerative/cardiometabolic/cardiovascular/gastrointestinal diseases, peritonitis, periodontitis, asthma and lung inflammation, Duchenne muscular dystrophy, SARS-CoV-2-induced inflammation, and placenta disorders. The idea of biological intervention through modulating GPR18 signalling is attracting growing attention because of its great therapeutic potential. With this paper, we aimed to present a comprehensive review of the most recent literature, perform a constructive view of data, and point out research gaps.

Keywords: GPR18; agonist; antagonist; inflammation; resolution; resolvin D2.

Figure 1

Structures of endogenous and natural agonists of GPR18. Data from ^a [18], ^b [19], ^c [20], ^d [16], ^e [21], ^f [22], ^g [13], ^h [23].

Figure 2

Biosynthesis of RvD2.

Figure 3

Synthesis of radiolabelled derivative of RvD2 ([10,11-³H]-RvD2-ME).

Figure 4

Observed metabolism of RvD2.

Figure 5

Structures of synthetic GPR18 agonists. * The structures are undisclosed and will be published elsewhere. Data from: ^a [19]; ^b [32];^c EP3901142.

Figure 6

Structures of selected synthetic GPR18 antagonists. Data from: ^a [13]; ^b [35]; ^c [34]; ^d [36]; ^e [27].

Figure 7

Omnidirectional effect of GPR18 activation in the resolution of inflammatory responses. PIC—pro-inflammatory cytokines; BBB—blood-brain barrier; MAPK—mitogen-activated protein kinase; NF-κB—nuclear factor kappa B; ROMO1—reactive oxygen species modulator 1; TRPV1—transient potential receptor vanilloid 1; DMP1—dentin matrix acidic phosphoprotein 1; WBC—white blood cells; MPO—myeloperoxidase. ↑ stimulatory/increased effect; ↓ downregulated/inhibited effect. Created with BioRender.com, accessed on 27 January 2024.