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 Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, and more recently defined maresins, are

12-lipoxygenase ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ''ALOX12'' gene which is located along with other lipoyxgenases on ...

-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 ...

docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(''n''−3). It can be synthesized from alpha-linolenic acid or ...

(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 Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...

(SPM) class of

polyunsaturated fatty acid In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...

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

epoxy Epoxy is the family of basic components or Curing (chemistry), cured end products of epoxy Resin, resins. Epoxy resins, also known as polyepoxides, are a class of reactive prepolymers and polymers which contain epoxide groups. The epoxide fun ...

-hydroxy metabolites of long chain PUFA made by certain

dioxygenase Dioxygenases are oxidoreductase enzymes. Aerobic organism, 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 energ ...

enzymes viz.,

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

s and

lipoxygenase Lipoxygenases () (LOX) are a family of (non- heme) iron-containing enzymes, more specifically oxidative enzymes, most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into ce ...

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 import ...

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. Funct ...

)-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-resolvi ...

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 (PUFA) that share a final carbon-carbon double bond in the ''n''−6 position, that is, the sixth bond, counti ...

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

; the cyclooxygenase 2-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 from two isomers of docosapentaenoic acid (DPA), one omega-3 and one ...

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 wi ...

; certain 15-lipoxygenase-derived resolvin 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 fat ...

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 open chain polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, ''all''-''cis''-4,7,10,13,16-docosapentaenoic acid (i.e. ...

(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.

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 monocyte-derived 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-HDHA); the

5-lipoxygenase Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...

-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''-docosahexaenoic 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 synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

. In a murine model of

acute respiratory distress syndrome Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin co ...

, MaR1 production was detected; its generation appeared to reflect an interaction between blood

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

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 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 carry out' (to the grave), extended meaning 'to bury') is the process by which apoptotic cells are removed by phagocytic cells. It can be regarded as the 'burying of dead cells'. Du ...

) of

apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...

human neutrophils by human macrophages, stimulates macrophage

phagocytosis Phagocytosis () is the process by which a cell (biology), 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 ph ...

, and limits the infiltration of neutrophils into the inflamed peritoneum of mice. In a murine model of

, 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 cell 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 immune tolerance, tolerance to self-antigens, and prevent autoimmune disease. Treg ...

s which interacted with Group 2

innate lymphoid cell Innate lymphoid cells (ILCs) are the most recently discovered family of Innate immune system, innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secreti ...

s (i.e. helper T cell lymphocytes) to markedly suppress the production of two

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

interleukin-5 Interleukin 5 (IL-5) 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 Ig ...

and interleukin-13, implicated in mediating allergic reactions. MaR1 accelerated tissue regeneration in experimentally injured planaria 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 (electrophysiol ...

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 ...

, and thereby blocking capsaicin-induced inward currents and neuron excitation. MaR2 possesses 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 in producing these responses are similar to those of MaR1. 13(''S''),14(''S'')-epoxy-maresin inhibits the production of the

metabolite,

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

(LTB₄), by directly inactivating the enzyme, leukotriene-A4 hydrolase, which converts the LTB₄ precursor,

leukotriene A4 Leukotriene A4 (LTA4) is a leukotriene Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid ...

, 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

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

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