Specialized pro-resolving mediators

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Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of

The production and activities of the SPM suggest a new view of inflammation wherein the initial response to foreign organisms, tissue injury, or other insults involves numerous soluble cell signaling molecules that not only recruit various cell types to promote inflammation but concurrently cause these cells to produce SPM which feed back on their parent and other cells to dampen their pro-inflammatory activity and to promote repair. Resolution of an inflammatory response is thus an active rather than self-limiting process which is set into motion at least in part by the initiating pro-inflammatory mediators (e.g. prostaglandin E2 and prostaglandin D2) which instruct relevant cells to produce SPM and to assume a more anti-inflammatory phenotype. Resolution of the normal inflammatory response, then, may involve switching production of pro-inflammatory to anti-inflammatory PUFA metabolites. Excessive inflammatory responses to insult as well as many pathological inflammatory responses that contribute to diverse diseases such as atherosclerosis, diabetes, Alzheimer's disease, inflammatory bowel disease, etc. (see Inflammation § Disorders) may reflect, in part, a failure in this class switching. Diseases caused or worsened by non-adaptive inflammatory responses may by amenable to treatment with SPM or synthetic SPM which, unlike natural SPM, resist in vivo metabolic inactivation.^[2][12][13] The SPM possess overlapping activities which work to resolve inflammation. SPMs (typically more than one for each listed action) have the following anti-inflammatory activities on the indicated cell types as defined in animal and human model studies:^{[1][14][15][16]}

• Neutrophils: inhibit their migration from the blood circulation into inflamed tissues and their release of tissue-injuring reactive oxygen species and granule-bound enzymes; stimulates their expression the chemokine receptor, CCR5, to inhibit chemokine signaling, enhances their phagocyte activity, and promotes their death by apoptosis.
• Eosinophils: inhibit their migration from the blood circulation into inflamed tissues.
• chemotactic factors
  and release of pro-inflammatory mediators.
• adaptive immune responses in T helper 17 cells; stimulates natural killer T cell lymphocytes to induce apoptosis in the neutrophils and eosinophil of inflamed tissues; and increases the cytotoxicity of the natural killer cell type of lymphocytes by, e.g. promoting their ability to induce apoptosis in neutrophils and eosinophils
  in inflamed tissues.
• clotting
  .
• Interleukin-10
  , more resistant to become apoptotic, and more active in leaving sites of inflammation.
• Microglia cells: inhibit the release of pro-inflammatory cytokines by this central nervous system type of macrophage.
• Mast cells: inhibit their infiltration into inflamed tissues and, in lung mast cells, the release of histamine.
• Dendritic cells: suppresses their migration to lymph nodes as well as their release of pro-inflammatory cytokines and expression of MHC class II proteins.
• dorsal root ganglia
  , and/or spinal cord thereby suppressing pain perception.

SPMs also stimulate anti-inflammatory and tissue reparative types of responses in epithelium cells, endothelium cells, fibroblasts, smooth muscle cells, osteoclasts, osteoblasts, goblet cells, and kidney podocytes^[1] as well as activate the heme oxygenase system of cells thereby increasing the production of the tissue-protective gaso-transmitter, carbon monoxide (see Carbon monoxide § Physiology), in inflamed tissues.^[17]

Biochemistry

SPM are metabolites of arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or n-3 DPA (i.e. 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid or clupanodonic acid); these metabolites are termed lipoxins (Lx), resolvins (Rv), protectins (PD) (also termed neuroprotectins [NP]), and maresins (MaR). EPA, DHA, and n-3 DPA are n-3 fatty acids; their conversions to SPM are proposed to be one mechanism by which n-3 fatty acids may ameliorate inflammatory diseases (see Omega-3 fatty acid § Inflammation).^[18] SPM act, at least in part, by either activating or inhibiting cells through binding to and thereby activating or inhibiting the activation of specific cellular receptors.

Lipoxins

Human cells synthesize LxA4 and LxB4 by serially metabolizing arachidonic acid (5Z,8Z,11Z,14Z-eicosatetraenoic acid) with a)

• The FPL2 receptor (also termed the ALX, ALX/FPR2 receptor) is expressed on human neutrophils, eosinophils, monocytes, macrophages, T cells, synovial fibroblasts, and intestinal and airway epithelium as well as on astrocytes in the spinal cord of mice; GPR32 (also termed the RvD1 receptor or DRV1)is expressed on human neutrophils, lymphocytes, monocytes, macrophages, and vascular tissue. Both of these receptors are involved in regulating inflammation.^[19][22] The AHR (i.e. the aryl hydrocarbon receptor) is a ligand-activated transcription factor that regulates xenobiotic-metabolizing enzymes such as cytochrome P450 enzymes.

Resolvins

Resolvins are metabolites of omega-3 fatty acids, EPA, DHA, and 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid (n-3 DPA). All three of these omega-3 fatty acids are abundant in salt water fish, fish oils, and other seafood.^[18] n-3 DPA (also termed clupanodonic acid) is to be distinguished from its n-6 DPA isomer, i.e. 4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid, also termed osbond acid.

EPA-derived resolvins

Cells metabolize EPA (5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid) by a cytochrome P450 monooxygenase(s) (in infected tissues a bacterial cytochrome P450 may supply this activity) or aspirin-treated cyclooxygenase-2 to 18R-hydroperoxy-EPA which is then reduced to 18R-hydroxy-EPA and further metabolized by ALOX5 to 5S-hydroperoxy-18R-hydroxy-EPA; the later product may be reduced to its 5,18-dihydroxy product, RvE2, or converted to its 5,6-epoxide and then acted on by an epoxide hydrolase to form a 5,12,18-trihydroxy derivative, RvE1. In vitro, ALOX5 can convert 18S-HETE to the 18S analog of RvE1 termed 18S-RvE1. 18R-HETE or 18S-HETE may also be metabolized by ALOX15 to its 17S-hydroperoxy and then reduced to its 17S-hydroxy product, Rv3. Rv3, as detected in in vitro studies, is a dihydroxy mixture of 18S-dihydroxy (i.e. 18S-RvE3) and 18R-dihydroxy (i.e. 18R-RvE3) isomers, both of which, similar to the other aforementioned metabolites possess potent SPM activity in in vitro and/or animal models.^[23][24][25] In vitro studies find that ALOX5 can convert 18S-hydroperoxy-EPA to the 18S-hydroxy analog of RvE2 termed 18S-RvE2. 18S-RvE2, however has little or no SPM activity^[25] and is therefore not considered to be a SPM here. The following table lists the structural formulae (EPA stands for eicosapentaenoic acid), major activities, and cellular receptor targets (where known).

• CMKLR1 (
  glutamate receptor and ion channel protein involved in controlling synaptic plasticity and memory.^[1][22][23]

Cells metabolize DHA (4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid) by either ALOX15 or a cytochrome P450 monooxygenase(s) (bacteria may supply the cytochrome P450 activity in infected tissues) or aspirin-treated cyclooxygenase-2 to 17S-hydroperoxy-DHA which is reduced to 17S-hydroxy-DHA. ALOX5 metabolizes this intermediate to a) 7S-hydroperoxy,17S-hydroxy-DHA which is then reduced to its 7S,17S-dihydroxy analog, RvD5; b) 4S-hydroperoxy,17S-hydroxy-DHA which is reduced to its 4S,17S-dihydroxy analog, RvD6; c) 7S,8S-epoxy-17S-DHA which is then hydrolyzed to 7,8,17-trihydroxy and 7,16,17-trihydorxy products, RvD1 and RvD2, respectively; and d) 4S,5S-epoxy-17S-DHA which is then hydrolyzed to 4,11,17-trihydroxy and 4,5,17-trihydroxy products, RvD3 and RvD4, respectively. These six RvDs possess a 17S-hydroxy residue; however, if aspirin-treated cyclooxygenase-2 is the initiating enzyme, they contain a 17R-hydroxy residue and are termed 17R-RvDs, aspirin-triggered-RvDs, or AT-RvDs 1 thru 6. In certain cases, the final structures of these AT-RvDs is assumed by analogy to the structures of their RvD counterparts. Studies have found that most (and presumably all) of these metabolites have potent anti-inflammatory activity in vitro and/or in animal models.^{[22][23][24][29]} The following table lists the structural formulae, major activities with citations and cellular receptor targets of D series resolvins.

• The distribution and major functions of GPR32, FPR2, TRPV1, and TRPV3 are given in the above EPA-derived resolvins section; TRPA1 is a chemosensor ion channel located on the plasma membrane of many human cell types; TRPV4, also termed the vanilloid-receptor related osmotically activated channel (VR-OAC) and OSM9-like transient receptor potential channel member 4 (OTRPC4)2], is involved in multiple physiologic functions and dysfunctions. With respect to the SPMS, both receptors mediate the perception of various forms of inflammation-triggered pain.^[1][23]
• The initial product of 15-lipoxygenase attack on DHA is 17S-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17-HpDHA) which may then be rapidly reduced by a cellular glutathione peroxidase to 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17-HDHA). 17-HDHA has potent anti-inflammatory activity and has been classified as a SPM although not a resolvin.^[33][34] Similarly, 14S,20R-dihyrdoxy-4Z,7Z,10Z,12E,16Z,18E-docosahexaenoic acid, while not yet assigned a RvD number, qualifies as a RvD-related SPM. It is a DHA metabolite made by mouse eosinophils, detected in the peritoneal fluid of mice undergoing experimental peritonitis, and possessing the ability to inhibit the influx of leukocytes into the peritoneum of the mice.^[24][35] Finally, two resolvin sulfido-conjugates (8-glutathionyl,7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid and 8-cysteinylglycinyl,7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid) have been shown to be formed from their 7,17-dihydroxy precursor by cells in vitro, to accelerate regeneration of experimental injuries in planaria worms, and to have potent anti-inflammatory activity in various in vitro model systems.^[36]

n-3 DPA-derived resolvins

n-3 DPA (i.e. 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid)-derived resolvins are recently identified SPM. In the model system used to identify them, human

Protectins/neuroprotectins

DHA-derived protectins/neuroprotectins

Cells metabolize DHA by either ALOX15, by a bacterial or mammalian

• The TRPV1 receptor is discussed in the EPA-derived resolvin section.
• While not yet given trivial names, certain isomers of the protectins also prove to have SPM activity: the 13Z
  cis-trans isomer of 10-epi-PD1, 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-DHA, is a relatively abundant metabolite compared to PD1 detected in the peritoneal fluid from a mouse model of peritonitis (although not detected in stimulated leukocytes) and has moderately potent anti-inflammatory activity in this model; 10R,17S-dihydroxy-4Z,7Z,11E,13E,15E,19Z-DHA, is a prominent metabolite detected in stimulated leukocytes, not detected the mouse peritonitis model, and has modest anti-inflammatory activity in the latter model; and 10S,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHA, while not detected by in the mouse model of peritonitis or stimulated leukocytes, is more potent than even PD1 in inhibiting peritonitis in the mouse model.^[45] In addition to these compounds, two protectin sulfido-conjugates (16-glutathionyl,17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid and 16-cysteinylglycinyl,17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid) form in vitro, accelerate regeneration of injured planaria worms, and have potent anti-inflammatory activity in in vitro model systems.^[36]

n-3 DPA-derived protectins with structural similarities to PD1 and PD2 have been described, determined to be formed in vitro and in animal models, and termed PD1_n-3 and PD2_n-3, respectively. These products are presumed to be formed in mammals by the metabolism of n-3 DPA by an unidentified 15-lipoxygenase activity to 16,17-epoxide intermediate and the subsequent conversion of this intermediate to the di-hydroxyl products PD1_n-3 and PD2_n-3. PD1_n-3 has anti-inflammatory activity in a mouse model of peritonitis; PD2_n-3 has anti-inflammatory activity in an in vitro model.^[38][46] The following table lists the structural formulae (DPA stands for docosapentaenoic acid), major activities and cellular receptor targets (where known).

Maresins

DHA-derived maresins

Cells metabolize DHA by ALOX12, other lipoxygenase, (12/15-lipoxygenase in mice), or an unidentified pathway to a 13S,14S-epoxide-4Z,7Z,9E,11E,16Z,19Z-DHA intermediate (13S,14S-epoxy-maresin MaR) and then hydrolyze this intermediate by an epoxide hydrolase activity (which ALOX 12 and mouse 12/15-lipoxygenase possess) to MaR1 and MaR2. During this metabolism, cells also form 7-epi-Mar1, i.e. the 7S-12E isomer of Mar1, as well as the 14S-hydroxy and 14R-hydroxy metabolites of DHA. The latter hydroxy metabolites can be converted by an unidentified cytochrome P450 enzyme to maresin like-1 (Mar-L1) and Mar-L2 by omega oxidation; alternatively, DHA may be first metabolized to 22-hydroxy-DHA by CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1, or CYP3A4 and then metabolized through the cited epoxide-forming pathways to Mar-L1 and MaR-L2. Studies have found that these metabolites have potent anti-inflammatory activity in vitro and in animal models.^[13][23][24] The following table lists the structural formulae (DHA stands for docosahexaenoic acid), major activities and cellular receptor targets (where known).

• Studies in mice detected a series of R/S 14,21-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid isomers (14R,21R-diHDHA, 14R,21S-diHDHA, 14S,21R-diHDHA, and 14S,21S-diHDHA) form in inflamed tissues and in cultures of murine macrophages; the 14R,21-diHDHA and 14S,21-diHDHA isomers promoted wound healing in mouse models of inflammation.^[13][48]
• Mouse eosinophils metabolize DHA to a maresin-like product, 14S,20R-dihydroxy-4Z,7Z,10Z,12E,16Z,18Z-docosahexaenoic acid. This product, as well as its 14,S,20S isomer possesses potent anti-inflammatory activity in mice.^[24]
• The TRPV1 receptor is discussed in the EPA-derived resolvin section; the TRPA1 receptor is discussed in the DHA-derived resolvin section.

n-3 DPA-derived maresins

n-3 DPA-derived maresins are presumed to be formed in mammals by metabolism of n-3 DPA by an undefined 12-lipoxygenase activity to a 14-hydroperoxy-DPA intermediated and the subsequent conversion of this intermediate to di-hydroxyl products which have been termed MaR1_n-3, MaR2_n-3, and MaR3_n-3 based on their structural analogies to MaR1, MaR2, and MaR3, respectively. MaR1_n-3 and MaR2_n-3 have been found to possess anti-inflammatory activity in in vitro assays of human neutrophil function. These n-3 DPA-derived maresins have not been defined with respect to the chirality of their hydroxyl residues or the cis–trans isomerism of their double bonds.^[38] The following table lists the structural formulae (DPA stands for docosapentaenoic acid), major activities and cellular receptor targets (where known).

Other PUFA metabolites with SPM-like activity

The following PUFA metabolites, while not yet formally classified as SPM, have been recently described and determined to have anti-inflammatory activity.

n-3 DPA metabolites

10R,17S-dihydroxy-7Z,11E,13E,15Z,19Z-docosapentaenoic acid (10R,17S-diHDPA_EEZ) has been found in inflamed exudates of animal models and possesses in vitro and in vivo anti-inflammatory activity almost as potently as PD1.^[43]

n-6-DPA metabolites

n-6 DPA (i.e. 4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid or osbond acid) is an

DHA ethanolamide ester (the DHA analog of arachindonyl ethanolamide (i.e. anandamide) is metabolized to 10,17-dihydroxydocosahexaenoyl ethanolamide (10,17-diHDHEA) and/or 15-hydroxy-16(17)-epoxy-docosapentaenoyl ethanolamide (15-HEDPEA) by mouse brain tissue and human neutrophils. Both compounds possess anti-inflammatory activity in vitro; 15-HEDPEA also has tissue-protective effects in mouse models of lung injury and tissue reperfusion. Like anandamide, both compounds activated the cannabinoid receptor.^[49][50]

Prostaglandins and isoprostanes

PUFA derivatives containing a cyclopentenone structure are chemically reactive and can form adducts with various tissue targets, particularly proteins. Certain of these PUFA-cyclopentenones bind to the sulfur residues in the

• N-Acylethanolamine

References