New Advances in Targeting the Resolution of Inflammation: Implications for Specialized Pro-Resolving Mediator GPCR Drug Discovery

Abstract

Chronic inflammation is a component of numerous diseases including autoimmune, metabolic, neurodegenerative, and cancer. The discovery and characterization of specialized pro-resolving mediators (SPMs) critical to the resolution of inflammation, and their cognate G protein-coupled receptors (GPCRs) has led to a significant increase in the understanding of this physiological process. Approximately 20 ligands, including lipoxins, resolvins, maresins, and protectins, and 6 receptors (FPR2/ALX, GPR32, GPR18, chemerin₁, BLT₁, and GPR37) have been identified highlighting the complex and multilayered nature of resolution. Therapeutic efforts in targeting these receptors have proved challenging, with very few ligands apparently progressing through to preclinical or clinical development. To date, some knowledge gaps remain in the understanding of how the activation of these receptors, and their downstream signaling, results in efficient resolution via apoptosis, phagocytosis, and efferocytosis of polymorphonuclear leukocytes (mainly neutrophils) and macrophages. SPMs bind and activate multiple receptors (ligand poly-pharmacology), while most receptors are activated by multiple ligands (receptor pleiotropy). In addition, allosteric binding sites have been identified signifying the capacity of more than one ligand to bind simultaneously. These fundamental characteristics of SPM receptors enable alternative targeting strategies to be considered, including biased signaling and allosteric modulation. This review describes those ligands and receptors involved in the resolution of inflammation, and highlights the most recent clinical trial results. Furthermore, we describe alternative mechanisms by which these SPM receptors could be targeted, paving the way for the identification of new therapeutics, perhaps with greater efficacy and fidelity.

Figure 1

Resolution of inflammation. Following insult, injury or infection acute inflammation develops. Edema, followed by polymorphonuclear neutrophils (PMN) infiltration, occurs within minutes to hours, closely followed by the resolution of inflammation by monocytes and macrophages over hours to days. Specialized pro-resolving mediators (SPMs), including lipoxins (LXA₄), resolvins (D- and E-series), maresins, and protectins, are biosynthesized to facilitate resolution. Figure generated from our interpretation of multiple reviews and research articles.^,,,,,

Figure 2

Specialized pro-resolving mediators (SPMs). Overview of lipoxins, resolvins, maresins, and protectins biosynthesized from omega-3 polyunsaturated fatty acids (PUFA) including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA).^,,,,,−,,,,

Figure 3

GPCRs activated by multiple subpopulation pro-resolving mediators. Pairing of SPMs and associate ligands to their cognate receptors have been much explored utilizing various methods including radioligand binding. Early research into SPM pharmacology focused primarily on the ligand activity; however, recent attention has shifted toward further elucidation of the signaling mechanism involved. To date, knowledge gaps remain in the signal transduction pathways leading to increasingly well-described physiological responses. Due to ligand poly-pharmacology and receptor pleiotropy, distinct opportunities to target these receptors via novel mechanisms exist, including biased signaling and allostery. Both mechanisms have been partially described for FPR2/ALX, but due to the vast number of SPMs and GPCRs identified, the combinations could be limitless, clearly highlighting significant opportunities in augmenting the resolution of inflammation. Figure generated from our interpretation of multiple reviews.^,,,,,,

Figure 4

Phylogenetic tree of the six human SPM GPCRs. The tree was generated using iTOL. cml1 = chemerin₁ and lt4r1 = BLT₁. GPR32 was identified as a receptor for RvD1, RvD3, AT-RvD3, and RvD5.^, Sharing a close phylogenetic identity with GPR32, FPR2/ALX was initially discovered as an fMLP receptor;^, However, the receptor was later reclassified as a receptor for LXA₄ due high affinity binding of this ligand. Chemerin₁ has recently been reclassified following the identification of its cognate ligand, chemerin.⁻ BLT1 binds numerous ligands including LTB₄, RvE1, and RvE2.^,, GPR18 still remains as an orphan receptor with several endogenous and SPM ligands having been identified, including NAGly and RvD2, but yet remaining to be confirmed. GPR37 has recently been identified as a receptor for neuroprotection D1 (NPD1).