Formation, Signaling and Occurrence of Specialized Pro-Resolving Lipid Mediators-What is the Evidence so far?

Nils Helge Schebb,Dieter Steinhilber,Dieter Steinhilber,Robert C Murphy,Nicolas Flamand,Nicolas Flamand,Claes Dahlgren,Valerie B O’Donnell,Marc Peters-Golden,Astrid S Kahnt,Per-Johan Jakobsson,Per-Johan Jakobsson,Mohamad Wessam Alnouri,Garret A Fitzgerald,Garret A Fitzgerald,Stefan Offermanns,Stefan Offermanns,Nadine Rohwer,Nadine Rohwer,Karsten H Weylandt,Gerd Geisslinger,Hartmut Kühn,Hartmut Kühn,Hartmut Kühn,Katharina M Rund,Julien Hanson

doi:10.3389/fphar.2022.838782

Abstract

Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation.

Highlights

Taken together, it has become evident that the 5-LO pathway is part of the innate and adaptive immune system
It should be noted that, in addition to the prominent differences that exist in gene expansion of formyl peptide receptors (FPRs) between humans and mice, there is increasing evidence indicating that human FPRs and their murine counterparts differ substantially with respect to their ligandbinding profiles, as illustrated by the fact that some of the potent and selective antagonists for the FPRs lack effects on the mouse receptors, and an earlier described FPR2/ALX inhibitor/antagonist activates FPR2/ALX (Winther et al, 2018)
The same group reported later that RvE2 binds to HEK cells overexpressing BLT1 and to reduce leukotriene B4 (LTB4)-induced βarrestin signaling (Oh et al, 2012). These findings suggest that RvE1 and RvE2 induce their effects through a partial agonism at the BLT1 receptor thereby dampening the pro-inflammatory effects of LTB4

Summary

Summary on SPM Biosynthesis Pathways

The proposed biosynthetic pathways for most SPMs involve 5-LO (ALOX5) as well as 12/15-LO activities (15-LO1, 15-LO2, 12LO). It should be noted that, in addition to the prominent differences that exist in gene expansion of formyl peptide receptors (FPRs) between humans and mice, there is increasing evidence indicating that human FPRs and their murine counterparts differ substantially with respect to their ligandbinding profiles, as illustrated by the fact that some of the potent and selective antagonists for the FPRs lack effects on the mouse receptors, and an earlier described FPR2/ALX inhibitor/antagonist activates FPR2/ALX (Winther et al, 2018) No such comparative studies of mice and men involving SPMs have been performed, which highlights the importance in future research studies of choosing appropriate ligands when designing animal experiments. MaR1-induced phagocytosis in human macrophages depended on LGR6 After conducting another screen of orphan GPCRs using the β-arrestin recruitment assay, ω-3 docosapentaenoic acid-derived resolvin D5 (RvD5n-3 DPA) was reported to be able to function through various GPCRs, of which GPR101 mediated the strongest effect (Flak et al, 2020). Several effects of RvD5n-3 DPA on macrophages were affected by knock-down of GPR101

Summary on SPM Receptors

Findings

CONCLUSION