Maresin 1 (MaR1 or 7''R'',14''S''-dihydroxy-4''Z'',8''E'',10''E'',12''Z'',16''Z'',19''Z''-docosahexaenoic acid) is a macrophage-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, and more recently defined maresins, are 12-lipoxygenase-derived metabolites of the

omega-3 fatty acid Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...

docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lin ...

(DHA), that possess potent anti-inflammatory, pro-resolving, protective, and pro-healing properties similar to a variety of other members of the

specialized proresolving mediators Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...

(SPM) class of

polyunsaturated fatty acid Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...

(PUFA) metabolites. SPM are dihydroxy, trihydroxy, and

epoxy Epoxy is the family of basic components or cured end products of epoxy resins. Epoxy resins, also known as polyepoxides, are a class of reactive prepolymers and polymers which contain epoxide groups. The epoxide functional group is also coll ...

-hydroxy metabolites of long chain PUFA made by certain

dioxygenase Dioxygenases are oxidoreductase enzymes. Aerobic life, from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on the oxidizing power of dioxygen in various metabolic pathways. From energetic adenosine tri ...

enzymes viz.,

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as pr ...

s and

lipoxygenase Lipoxygenases () are a family of (non-heme) iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as aut ...

s. In addition to the maresins, this class of mediators includes: the 15-lipoxygenase (i.e.

ALOX15 ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically importa ...

and/or possibly

ALOX15B Arachidonate 15-lipoxygenase type II is an enzyme that in humans is encoded by the ''ALOX15B'' gene. ALOX15B, also known as 15-lipoxygenase-2 (15-LO-2 or 15-LOX-2), is distinguished from its related oxygenase, ALOX15 or 15-lipoxygenase-1. Fun ...

)-derived

Lipoxin A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolvin ...

A₄ and B₄ metabolites of the

omega 6 fatty acid Omega-6 fatty acids (also referred to as ω-6 fatty acids or ''n''-6 fatty acids) are a family of polyunsaturated fatty acids that have in common a final carbon-carbon double bond in the ''n''-6 position, that is, the sixth bond, counting from ...

, arachidonic acid; the

cyclooxygenase 2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...

-derived

Resolvin Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. As autacoids similar ...

E series metabolites of the omega 3 fatty acid,

eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-c ...

; certain 15-lipoxygenase-derived

D series metabolites of DHA; certain other 15-lipoxygenase-derived

protectin D1 Protectin D1 also known as neuroprotectin D1 (when it acts in the nervous system) and abbreviated most commonly as PD1 or NPD1 is a member of the class of specialized proresolving mediators. Like other members of this class of polyunsaturated fa ...

and related metabolites of DHA; and the more recently defined and therefore less fully studied 15-lipoxygenase-derived Resolvin D_n-3DPA metabolites of the omega-3 fatty acid n-3

docosapentaenoic acid Docosapentaenoic acid (DPA) designates any straight chain 22:5 fatty acid, that is a straight chain open chain type of polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, ...

(n-3 DPA or clupanodonic acid), the cyclooxygenase 2-derived Resolvin T metabolites of this clupanodonic acid, and the 15-lipoxygenase-derived products of the N-acetylated fatty acid amide of the DHA metabolite, docosahexaenoyl ethanolamide (see

resolvin Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. As autacoids similar ...

s).

Production

MaR1 was first defined as a product of DHA formed by cultures of human

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

-derived macrophages. Studies implicate the following pathway in its formation: 12-lipoxygenase converts DHA to its 14-hydroxperoxy intermediate, 14(''S'')-hydroperoxy-4''Z'',7''Z'',10''Z'',12''E'',16''Z'',19''Z''-DHA (14-HpDHA); 14-HpDHA is converted enzymatically to its 13(''S''),14(''S'')

derivative, termed 13(''S''),14(''S'')-epoxy-maresin which is then enzymatically hydrolyzed to Mar1. Byproducts of this metabolism include the reduction of 14-HpDHA to its hydroxyl counterpart, 14(''S'')-hydroxy-4''Z'',7''Z'',10''Z'',12''E'',16''Z'',19''Z''-DHA (14-HDPA); the 5-lipoxygenase-dependent conversion of 14-HpDHA and/or 14-HDHA to 7(''S''),14(''S'')-dihydroxy-4''Z'',8''E'',10''Z'',12''E'',15''Z'',19''Z''-DHA; and the non-enzymatic hydrolysis of 14-HpDHA to 7(''S''/''R''),14(''S'')-DHA and 13(''S''/''R'')-DHA products. Concurrently, the macrophages also convert DHA to 13(''R''),14(''S'')-dihydroxy-4''Z'',7''Z'',9''E'',11''E'',16''Z'',19''Z''-docosapentaenoic acid, i.e. maresin 2 (MaR2). The measurement of 17-HDHA in tissues is used as a marker for the level of activation of the maresin-producing pathway.

Sources

The maresins have been detected primarily as products made by monocyte-macrophage cells types. MaR1 has been identified in the synovial fluid taken from the joints of patients with

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

. In a murine model of acute respiratory distress syndrome, MaR1 production was detected; its generation appeared to reflect an interaction between blood platelets and neutrophils wherein 12-lipoxygenase-rich platelets generated 13(''S''),14(''S'')-epoxy-maresin which was then passed to neutrophils which hydrolyzed the epoxy maresin to MaR1.

Planaria ''Planaria'' is a genus of planarians in the family Planariidae. When an individual is cut into pieces, each piece has the ability to regenerate into a fully formed individual. Description Currently the genus ''Planaria'' is defined as fres ...

worms metabolize DHA to Mar1 during the healing phase of experimentally induced tissue injury.

Activities

Studies suggest that maresins are involved in resolving inflammatory and allergic reactions, in wound healing, and in abating neuropathic pain. Mar1 enhances the uptake (i.e. stimulates the

efferocytosis In cell biology, efferocytosis (from ''efferre'', Latin for 'to take to the grave', 'to bury') is the process by which apoptotic cells are removed by phagocytic cells. It can be regarded as the 'burying of dead cells'. During efferocytosis, the c ...

) of

apoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...

human neutrophils by human macrophages, stimulates macrophage

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

, and limits the infiltration of neutrophils into the inflamed peritoneum of mice. In a murine model of acute respiratory distress syndrome, MaR1 generation was detected in a temporally regulated manner with early MaR1 production was dependent on platelet-neutrophil interactions; intravascular MaR1 was organ-protective, leading to decreased lung neutrophils, edema, tissue hypoxia, and prophlogistic mediators. In a murine model of a self-limiting pulmonary allergic reaction, MaR1 reduced lung inflammation. It appeared to act at least in part by augmenting the generation of

regulatory T cells The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosu ...

which interacted with Group 2 innate lymphoid cells (i.e. Helper T cell lymphocytes, see Innate lymphoid cell#GroupILC) to markedly suppress the production of two cytokines,

Interleukin-5 Interleukin 5 (IL5) is an interleukin produced by type-2 T helper cells and mast cells. Function Through binding to the interleukin-5 receptor, interleukin 5 stimulates B cell growth and increases immunoglobulin secretion - primarily IgA. I ...

and

Interleukin-13 Interleukin 13 (IL-13) is a protein that in humans is encoded by the ''IL13'' gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The second ...

, implicated in mediating allergic reactions. MaR1 accelerated tissue regeneration in experimentally injured

planaria ''Planaria'' is a genus of planarians in the family Planariidae. When an individual is cut into pieces, each piece has the ability to regenerate into a fully formed individual. Description Currently the genus ''Planaria'' is defined as fres ...

worms. In particular, it increasing the rate of head reappearance in beheaded worms. And, MaR1 reduced neuropathic pain in a mouse model by inhibiting a neuron

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...

TRPV1 The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the ''TRPV1'' gene. It was the first isolated member of th ...

, and thereby blocking capsaicin-induced inward currents and neuron excitation. Mar2 possess at least some of the activities ascribed to MaR1. It enhances human macrophage phagocytosis of particles and efferocytosis of apoptotic human neutrophils and reduces neutrophil infiltration into the inflamed peritoneum of mice. Its potencies ins producing these responses are similar to those of MaR1. 13(''S''),14(''S'')-epoxy-maresin inhibits the production of the arachidonic acid metabolite,

Leukotriene B4 Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice. Biochemistry Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It is produced from leukocytes in r ...

(LTB₄), by directly inactivating the enzyme,

Leukotriene-A4 hydrolase Leukotriene A4 hydrolase, also known as LTA4H is a human gene. The protein encoded by this gene is a bifunctional enzyme () which converts leukotriene A4 to leukotriene B4 and acts as an aminopeptidase. Function This enzyme belongs to the family ...

, which converts the LTB₄ precursor,

Leukotriene A4 Leukotriene A4 (LTA4) is a leukotriene, and is the precursor for the productions of LTB4 (leukotriene B)) and LTC4 (leukotriene C4). Biosynthesis of Leukotriene A4 Following the biosynthesis of eicosanoid, triggered as a result of infection or ...

, to LTB₄; this effect may contribute to the resolution of inflammatory responses by reducing the production of the proinflammatory mediator, LTB₄.

Clinical relevancy

Studies find that the maresins inhibit certain pro-inflammatory functions in human neutrophils and macrophages in vitro, that MaR1 and Mar2 reduce the entry of blood neutrophils into the inflamed peritoneum in a mouse model, and that Mar1 promotes the resolution of allergic pulmonary inflammation in a mouse model as well as wound healing in planaria worm model. These studies have not yet translated to human physiology or pathology. It is noted that MaR1 is detectable in the synovial fluid of patients with rheumatoid arthritis. It is also noted that macrophages derived by culturing the monocytes isolated from the blood of patients with

Localized aggressive periodontitis Aggressive periodontitis describes a type of periodontal disease and includes two of the seven classifications of periodontitis as defined by the 1999 classification system: # Localized aggressive periodontitis (LAP) # Generalized aggressive periodo ...

have reduced levels of 12-lipoxygenase and MaR1 as well as reduced phagocytosis and killing of the periodontal pathogenic bacteria,

Porphyromonas gingivalis ''Porphyromonas gingivalis'' belongs to the phylum ''Bacteroidota'' and is a nonmotile, Gram-negative, rod-shaped, anaerobic, pathogenic bacterium. It forms black colonies on blood agar. It is found in the oral cavity, where it is implicate ...

and

Aggregatibacter actinomycetemcomitans ''Aggregatibacter actinomycetemcomitans'' is a Gram-negative, facultative anaerobe, nonmotile bacterium that is often found in association with localized aggressive periodontitis, a severe infection of the periodontium. It is also suspected to b ...

; the latter functional defects were improved by treating the cells with MaR1. MaR1 also reduced inflammation in a mouse model of multiple sclerosis.Sánchez-Fernández, A., Zandee, S., Mastrogiovanni, M. et al. Administration of Maresin-1 ameliorates the physiopathology of experimental autoimmune encephalomyelitis. J Neuroinflammation 19, 27 (2022). https://doi.org/10.1186/s12974-022-02386-1 Further studies are needed to determine if maresins play a functional role in resolving inflammation, promoting wound healing, or limiting neuropathic pain and/or if maresins or their metabolism-resistant analogs are clinically useful in treating the latter conditions.

References

{{Reflist Lipids Docosanoids