Specialized pro-resolving mediators

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.
SPM join the long list of other physiological agents which tend to limit inflammation including glucocorticoids, interleukin 10, interleukin 1 receptor antagonist, annexin A1, carbon monoxide, nitric oxide, and hydrogen sulfide.
The absolute, as well as relative roles, of the SPM along with other physiological anti-inflammatory agents in resolving human inflammatory responses remain to be defined precisely. Studies suggest that synthetic SPM that are resistant to being metabolically inactivated hold promise of being clinically useful pharmacological tools for preventing and resolving a wide range of pathological inflammatory responses along with the tissue destruction and morbidity that these responses cause. Based on animal model studies, the inflammation-based diseases which may be treated by such metabolically resistant SPM analogs include not only pathological and tissue damaging responses to invading pathogens but also a wide array of pathological conditions in which inflammation is a contributing factor such as allergic inflammatory diseases, autoimmune diseases, psoriasis, atherosclerosis disease leading to heart attacks and strokes, type 1 and type 2 diabetes, the metabolic syndrome, and certain dementia syndromes.
Many of the SPM are metabolites of omega−3 fatty acids and have been proposed to be responsible for the anti-inflammatory actions that are attributed to omega−3 fatty acid-rich diets.

History

Through most of its early period of study, acute inflammatory responses were regarded as self-limiting innate immune system reactions to invading foreign organisms, tissue injuries, and other insults. These reactions were orchestrated by various soluble signaling agents such as a) foreign organism-derived N-formylated oligopeptide chemotactic factors complement components C5a and C3a which are chemotactic factors formed during the activation of the host's blood complement system by invading organisms or injured tissues; and c)''' host cell-derived pro-inflammatory cytokines, host-derived pro-inflammatory chemokines, platelet-activating factor, and PUFA metabolites including in particular leukotrienes, hydroxyeicosatetraenoic acids, the hydroxylated heptadecatrienoic acid, 12-HHT, and oxoeicosanoids. These agents functioned as pro-inflammatory signals by increasing the permeability of local blood vessels; activating tissue-bound pro-inflammatory cells such as mast cells, and macrophages; and attracting to nascent inflammatory sites and activating circulating neutrophils, monocytes, eosinophils, gamma delta T cells, and natural killer T cells. The cited cells then proceeded to neutralize invading organisms, limit tissue injury, and initiate tissue repair. Hence, the classic inflammatory response was viewed as fully regulated by the soluble signaling agents. That is, the agents formed, orchestrated an inflammatory cell response, but then dissipated to allow resolution of the response. In 1974, however, Charles N. Serhan, Mats Hamberg and Bengt Samuelsson, discovered that human neutrophils metabolize arachidonic acid to two novel products that contain 3 hydroxyl residues and 4 double bonds viz., 5,6,15-trihydroxy-7,9,11,13-icosatetraenoic acid and 5,14,15-trihydroxy-6,8,10,12-icosatetraenoic acid. These products are now termed lipoxin A4 and B4, respectively. While initially found to have in vitro activity suggesting that they might act as pro-inflammatory agents, Serhan and colleagues and other groups found that the lipoxins as well as a large number of newly discovered metabolites of other PUFA possess primarily if not exclusively anti-inflammatory activities and therefore may be crucial for causing the resolution of inflammation. In this view, inflammatory responses are not self-limiting but rather limited by the formation of a particular group of PUFA metabolites that counteract the actions of pro-inflammatory signals. Later, these PUFA metabolites were classified together and termed specialized pro-resolving mediators.

Inflammation

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 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, obesity, diabetes, Alzheimer's disease, inflammatory bowel disease, etc. 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. The SPM possess overlapping activities which work to resolve inflammation. SPMs have the following anti-inflammatory activities on the indicated cell types as defined in animal and human model studies:

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.
Monocytes: inhibit their migration response to chemotactic factors and release of pro-inflammatory mediators.
Lymphocytes: Inhibit the infiltration of CD4+ and CD8+ lymphocytes into inflamed sites and inhibits production of the pro-inflammatory signals, interleukin-4 and interferon gamma by CD4+ lymphocytes; promotes the apoptosis of Th-17 pro-inflammatory lymphocytes; promotes B cell lymphocytes to differentiate into antibody secreting cells; inhibits innate lymphoid cells from releasing pro-inflammatory cytokines such as interleukin-13 while stimulating them to secrete amphiregulin, a product which acts to restore mucosal integrity; Inhibits the production of the pro-inflammatory cytokines, interleukin-17 and interleukin-23, thereby contributing to the dampening 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.
Platelets: inhibit their aggregation and possibly thereby their contribution to blood clotting.
Macrophages: inhibit their infiltration into inflamed tissues and release of pro-inflammatory cytokines; stimulate their conversion from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype that are more active in secreting the anti-inflammatory cytokine, 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.
Neurons: act through their target G protein–coupled receptors to inhibit pain receptors on neurons in the peripheral nervous system, 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 as well as activate the heme oxygenase system of cells thereby increasing the production of the tissue-protective gaso-transmitter, carbon monoxide, in inflamed tissues.

Biochemistry

SPM are metabolites of arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, or n−3 DPA ; these metabolites are termed lipoxins, resolvins, protectins , and maresins. 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. 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 ALOX15 ALOX5 followed by ALOX15 ALOX5 followed by ALOX12. Cells and, indeed, humans treated with aspirin form the 15R-hydroxy epimer lipoxins of these two 15S-lipoxins viz., 15-epi-LXA4 and 15-epi-LXB4, through a pathway that involves ALOX5 followed by aspirin-treated cyclooxygenase-2. Aspirin-treated COX-2, while inactive in metabolizing arachidonic acid to prostanoids, metabolizes this PUFA to 15R-hydroperoxy-eicosatetraenoic acid whereas the ALOX15 pathway metabolizes arachidonic acid to 15S-hydroperoxy-eicosatetraenoic acid. The two aspirin-triggered lipoxins' or epi-lipoxins differ structurally from LxA4 and LxB4 only in the S'' versus R chirality of their 15-hydroxyl residue. Numerous studies have found that these metabolites have potent anti-inflammatory activity in vitro and in animal models and in humans may stimulate cells by binding to certain receptors on these cells. The following table lists the structural formulae, major activities, and cellular receptor targets.

Trivial name	Formula	Activities	Receptor
LxA4	5S,6R,15S-trihydroxy-7E,9E,11Z,13E-ETE	Anti-inflammatory, blocks pain perception	Stimulates FPR2, AHR
LxB4	5S,14R,15S-trihydroxy-6E,8Z,10E,12E-ETE	Anti-inflammatory, blocks pain perception	?
15-epi-LxA4	5S,6R,15R-trihydroxy-7E,9E,11Z,13E-ETE	Anti-inflammatory, blocks pain perception	stimulates FPR2
15-epi-LxB4	5S,14R,15R-trihydroxy-6E,8Z,10E,12E-ETE	Anti-inflammatory, blocks pain perception	?

The FPL2 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 is expressed on human neutrophils, lymphocytes, monocytes, macrophages, and vascular tissue. Both of these receptors are involved in regulating inflammation. The AHR is a ligand-activated transcription factor that regulates xenobiotic-metabolizing enzymes such as cytochrome P450 enzymes.