Specialized pro-resolving mediator network: an update on production and actions

Abstract

Today, persistent and uncontrolled inflammation is appreciated to play a pivotal role in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other diseases of public health concern (e.g. Coronavirus Disease 2019 (COVID-19) and periodontal disease). The ideal response to initial challenge in humans is a self-limited inflammatory response leading to complete resolution. The resolution phase is now widely recognized as a biosynthetically active process, governed by a superfamily of endogenous chemical mediators that stimulate resolution of inflammatory responses, namely specialized proresolving mediators (SPMs). Because resolution is the natural ideal response, the SPMs have gained attention. SPMs are mediators that include ω-6 arachidonic acid-derived lipoxins, ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvins, protectins and maresins, cysteinyl-SPMs, as well as n-3 docosapentaenoic acid (DPA)-derived SPMs. These novel immunoresolvents, their biosynthetic pathways and receptors have proven to promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via specific cellular and molecular mechanisms. As of 17 August, 2020, PubMed.gov reported >1170 publications for resolvins, confirming their potent protective actions from many laboratories worldwide. Since this field is rapidly expanding, we provide a short update of advances within 2-3 years from human and preclinical animal studies, together with the structural-functional elucidation of SPMs and identification of novel SPM receptors. These new discoveries indicate that SPMs, their pathways and receptors could provide a basis for new approaches for treating inflammation-associated diseases and for stimulating tissue regeneration via resolution pharmacology and precision nutrition.

Keywords: Eicosanoids; G-protein-coupled receptors; Inflammation; Resolution; Resolvins; leukocytes.

Figure 1.. Illustration of resolution metabolome: SPM biosynthesis, receptors and inactivation

Precursors EPA, DHA and n-3 DPA are converted via biosynthetic enzymes to SPMs, which activate their specific receptors to stimulate pro-resolving immune functions. The SPMs are rapidly enzymatically converted to metabolites with diminished or reduced activity.

Figure 2.. SPM receptor networks

SPMs stimulate resolution via activating cell surface GPCRs. RvE1 activates ERV1/ChemR23, leading to phosphorylation of Akt/S6 protein pathways that stimulates macrophage phagocytosis. RvD1 activates both DRV1/GPR32 and ALX, leading to regulation of microRNAs and their target genes, increases of efferocytosis (macrophage phagocytosis of apoptotic PMN) and M2 macrophage polarization. RvD2 activates GPR18, leading to cAMP release and phosphorylation of select kinases and transcription factors, essential for macrophage phagocytosis. Besides phagocytes, SPMs also display cell type-specific actions. For example, RvE1 activates both ERV1/ChemR23 and BLT1 on human conjunctival goblet cells to stimulate mucin secretion (158). 17R-RvD1 attenuates vascular smooth muscle cell migration via ALX/FPR2 and cAMP/PKA activity (159). RvD2-GPR18 axis enhances wound repair with human on keratinocytes (70). See text and earlier reviews (42, 112) for further details.

Figure 3.. Temporal phases in inflammation-resolution and SPM actions in preclinical animal disease models.

In in vivo animal diseases, select SPMs not only control classic non-resolving inflammation conditions, but also reduce collateral damages such as tissue and organ injuries, chronic pain and tissue fibrosis. They are normally active in picogram to low nanogram quantities, that is 100–1000x more potent than widely used classic NSAID. In the case of controlling pain, RvE1 is 1000X more potent than morphine (160). As potent agonists i.e. immunoresolvents, SPMs promote resolution and homeostasis via limiting excessive inflammatory responses (e.g. limiting PMN infiltration and cytokine storm), and enhancing efferocytosis, bacterial clearance, wound repair as well as tissue regeneration, defining the signs of resolution.

Figure 4.. Microvascular thrombosis and the roles of SPMs

Illustration of the intraluminal production and action of SPMs; PMN-platelet interactions initiate production of lipoxins and other SPMs, e.g. MaR1 (reviewed in 4). Microvesicles released from PMN also contribute to SPM formation (reviewed in 25). Select SPMs including LXA₄, MaR1, RvD1 and RvD4 enhance thrombus resolution, and RvD4 reduces NETosis (81).