European Review for Medical and Pharmacological Sciences 2020; 24: 7442-7453 Maresins: anti-inflammatory pro-resolving mediators with therapeutic potential Q.- F. LI1, H. HAO2, W.-S. TU1, N. GUO1, X.-Y. ZHOU3,4 1The First Clinical Medical College, Nanchang University, Nanchang, P.R. China 2Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, P.R. China 3Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China 4Jiangxi Province Key Laboratory of Tumor pathogenesis and Molecular Pathology, Nanchang, Jiangxi, P.R. China Qi-Fan Li and Hua Hao equally contributed to this paper Abstract. – Although inflammation is protec- nized as an important factor in chronic diseases tive of the body, uncontrolled acute inflammato- such as metabolic syndrome, cardiovascular dis- ry reactions may inflict tissue damage and lead ease, and nervous system diseases4-8, and it has to chronic inflammation. There is a fast-grow- therefore become a major public health concern. ing research interest in mechanisms that me- Anti-inflammatory mediators form a class of fac- diate regression of inflammation and actions of tors preventing further inflammation and tissue anti-inflammatory factors. Studies of inflamma- 9 tory and anti-inflammatory mechanisms have damage . The therapeutic use of anti-inflamma- uncovered roles for new lipid mediators, in- tory mediators may reduce inflammation-induced cluding lipoxins, resolvins, protectins, and ma- damage and have curative effects on the resulting resins, collectively referred to as specialized chronic diseases. pro-resolving mediators (SPM). Maresins have Fatty acids act as metabolic fuels for the recently been discovered and are biosynthe- human body and form an important part of the sized from docosahexaenoic acid (DHA) by mac- 10 rophages and display strong anti-inflammatory cell membrane . Besides these functions, fatty and pro-resolving activities. Here, we summa- acids affect human health by acting as signal- rize the actions and mechanisms of maresins in ing molecules11. They not only have an impact different diseases and suggest possible thera- on the health of cardiovascular diseases but peutic uses. also have impacts in a range of other diseases, Key Words: including metabolic and inflammatory diseas- 12 Inflammation, Lipid mediators, Maresins. es, and cancer . ω-6 Fatty acids (e.g., linoleic acid; LA) and ω-3 fat acids (e.g., α-linolenic acid; ALA) are essential fatty acids that can- not be synthesized by humans or other higher Introduction animals13. After a series of complex desatura- tion-and elongation reactions acting in concert Although inflammation is a predominantly to transform LA and ALA to their higher un- self-protective bodily response, acute excessive saturated derivatives: arachidonic acid (AA) levels of inflammation may cause great damage from LA, eicosapentaenoic acid (EPA) and to our health1. The inflammatory response in- docosahexaenoic acid (DHA) from ALA14,15. volves interactions between many different cell The conversion pathways are shown in Figure types and cytokines2. Typical symptoms accom- 1, and the produced derivatives will undergo panying inflammatory responses include fever, further biochemical processing in the body and redness, swelling, pain and loss of function3. are converted into molecules that affect metab- Today, excessive inflammation is widely recog- olism directly. 7442 Corresponding Author: Xiaoyan Zhou, Ph.D; e-mail: [email protected] Maresins: anti-inflammatory pro-resolving mediators with therapeutic potential Figure 1. The production of biosynthesis of pro-resolving lipid mediators. Abbreviation: 5/12/15-LOX, 5/12/15-Lipoxygenase; COX-2, Cyclooxygenase-2; RvD, resolving D series; RvE, resolving E series; MaR, maresin; PD1, Protectin D1; PDX, Protectin DX; LXA4, Lipoxin A4; LXB4, Lipoxin B4. SPMs are derived from essential fatty acids from the simplest ω-3 fatty acid, ALA, are es- and play crucial roles in orchestrating the reso- pecially abundant in e.g., fish oils, and play lution of tissue inflammation16. The new pro-re- important roles in organ function and health28. solving lipid mediators include separate families In humans, metabolites of PUFAs are known to of molecules: lipoxins, resolvins, protectins and trigger inflammation. However, prostaglandin E3 maresins, which are derived from AA and ome- and leukotriene B5 produced by ω-3 PUFAs are ga-3 polyunsaturated fatty acids17-20. Lipoxins and much less biologically active than the prosta- aspirin-triggered lipoxins, generated from AA, glandin E2 and leukotriene B4 produced by ω-6 reduce inflammation and promote resolution. In PUFAs 29. Furthermore, lipid mediators such as contrast, resolvins, maresins and protectins are resolvins and protectins produced by EPA and derived from omega-3 polyunsaturated fatty ac- DHA metabolism promote the regression of in- id21,22. Maresins are a class of 14S-dihydrox- flammation30. yl-containing molecules with conjugated triene Maresins form the third-largest family of double bonds, which are synthesized from DHA SPMs derived from DHA20. The biosynthesis of through an oxidative (e.g., lipoxygenase-relat- maresins occurs primarily in M2 macrophages ed) pathway during inflammation regression23. and is initiated by a reaction involving human In general, the biosynthesis of maresins occurs macrophage 12-lipoxygenase (12-LOX)31. The li- in M2 macrophages24. Abdulnour et al25 report poxygenation reaction involves insertion of an that maresin 1 is synthesized in the interaction of oxygen atom into DHA on the fourteenth carbon platelets with neutrophils. This review addresses atom. This generates 14S-HpDHA, which is fur- the contributing roles of maresins to the regres- ther transformed into 13S,14S-epoxide maresin, sion of inflammation and highlights their poten- followed by a conversion, performed by different tially beneficial roles in the resolution of various enzymes, e.g., maresin 1, maresin 2, and maresin diseases. conjugate in tissue regeneration (MCTR)32. Maresin 1 was the first discovered member Biosynthesis and Stereochemistry of the family of maresins33. By the action of Polyunsaturated fatty acids (PUFAs) play an 12-LOX, DHA was found to be converted to important role in the initiation, development and 14S-HpDHA 34. 12-LOX is a key enzyme in the regression of inflammation26,27. Two classes of synthesis of maresins35. When 12-LOX is absent PUFAs are distinguished: n-3 (ω-3) PUFAs and in macrophages, the production of 14S-HpDHA n-6 (ω-6) PUFAs15. DHA and EPA are derived is reduced by > 95%. By the action of 12-LOX, 7443 Q.-F. Li, H. Hao, W.-S. Tu, N. Guo, X.-Y. Zhou 14S-HpDHA is converted to 13S,14S-epoxy-ma- tion, oxidative stress and immune diseases. As resin. Next, by an epoxide-hydrolysis reaction, far as the current research proves, the cell actions the double bond in the 13S, 14S-epoxy-maresin is of maresins mainly promote the polarization and reconfigured to a Z/E configuration, yielding the phagocytosis of M2 macrophages41, inhibit the final product 7R, 14S-dihydroxydocosa-4Z, 8E, infiltration of neutrophils25, and induce Treg gen- 10E, 12Z, 16Z, 19Z-hexaenoic acid (maresin 1). eration42. Maresin 1 inhibits the differentiation of In addition, maresin 1 is produced by combined naive T cells into T-helper 1 (TH1) and T-help- actions of platelets and neutrophils25. Through er 17 (TH17) and promotes differentiation into the action of 12-LOX in platelets, DHA is con- Treg43. In various inflammatory environments, verted into 13S, 14S-epoxy-maresin, which is maresins inhibit the expression of pro-inflam- then transformed into maresin 1 by neutrophils. matory cytokines such as IL-6, TNF-α and IL- The substrates and initial steps for the biosyn- lβ by inhibiting TLR4/MAPK/NF-κB signaling thesis of maresin 2 are the same as for maresin pathway. Not only that, maresins can inhibit 1. The difference is that when DHA is converted the expression of TGF-β1, thereby inhibiting the to the intermediate 13S,14S-epoxy-maresin, it is phenotype transformation of fibroblasts by inhib- oxidized to 13R,14S-dihydroxy-docosahexaenoic iting the ERK/Smad signaling pathway. Maresins acid (13R, 14S-diHDHA) (maresin 2) by soluble increase the expression of oxidoreductase and epoxide hydrolase (sEH) within human macro- detoxification enzymes by activating the Nrf-2 phages36. MCTR is a conjugate in the process of signaling pathway, while reducing ROS genera- maresin-induced tissue regeneration, including tion by inhibiting the NF-κB signaling pathway44. MCTR1 (13R-glutathionyl, 14S-hydroxy-4Z, 7Z, By activating AMPK and PPARα, which can in- 9E, 11E, 13R, 14S, 16Z, 19Z-docosahexaenoic hibit endoplasmic reticulum (ER) stress, thereby acid), MCTR2 (13R-cysteinylglycinyl, 14S-hy- protecting the body. The molecular identifica- droxy-4Z, 7Z, 9E, 11E, 13R, 14S, 16Z, 19Z-do- tion of mareisns signal through its receptor has cosahexaenoic acid), MCTR3 (13R-cysteinyl, not yet been identified. The actions of maresins 14S-hydroxy-4Z, 7Z, 9E, 11E, 13R, 14S, 16Z, were shown in Figure 3. Inferred from current 19Z-docosahexaenoic acid)37. The biosynthesis of research, maresin 1 blocked transient receptor MCTRs (like that of maresins 1 and 2) is initiated potential V1-mediated currents in neurons45, acts by 12-LOX. The 13S, 14S-epoxy-maresin is con- as a ligand for Retinoid related orphan receptor α verted to MCTR1 by the catalysis of glutathione (RORα), inhibits TLR4 signaling. Chiang et al46 S-transferase MU 4 (GSTM4) and leukotriene has revealed that maresin 1 can activate LGR6, C4 synthase (LTC4S). MCTR1 is a precursor of a member of the glycoprotein hormone receptor MCTR2 and is converted to MCTR2 under the subfamily of rhodopsin-like GPCR, which ini- catalysis of gamma-glutamyl transferase (GGT). tiates cAMP and impedance change, as well as The biosynthesis of MCTR3 is based on MC- stimulates innate immune responses on PMN, TR2, with the catalysis of dipeptidases (DPEP), monocytes, and MΦ. Further research may reveal MCTR2 is converted to MCTR338. Conversion the receptors and mechanisms of maresins. relationship between DHA and maresin isomers is shown in Figure 2.