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Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions.

Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, Oh SF, Spite M - J. Exp. Med. (2008)

Bottom Line: Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MPhis).Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MPhi mediator in resolving inflammation (maresin), which enhances resolution.These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MPhis in tissue homeostasis, inflammation resolution, wound healing, and host defense.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. cnserhan@zeus.bwh.harvard.edu

ABSTRACT
The endogenous cellular and molecular mechanisms that control acute inflammation and its resolution are of wide interest. Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MPhis). During the resolution of mouse peritonitis, exudates accumulated both 17-hydroxydocosahexaenoic acid, a known marker of 17S-D series resolvin (Rv) and protectin biosynthesis, and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid from endogenous DHA. Addition of either DHA or 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid to activated MPhis converted these substrates to novel dihydroxy-containing products that possessed potent antiinflammatory and proresolving activity with a potency similar to resolvin E1, 5S,12R,18R-trihydroxyeicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, and protectin D1, 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MPhi mediator in resolving inflammation (maresin), which enhances resolution. These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MPhis in tissue homeostasis, inflammation resolution, wound healing, and host defense.

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Biosynthetic scheme proposed for MaR1 and related products. Stereochemistries and double-bond geometries of the new dihydroxy-containing mediators are tentative assignments and depicted in likely configurations based on biogenic synthesis, trapping, and labeling (see Results).
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fig5: Biosynthetic scheme proposed for MaR1 and related products. Stereochemistries and double-bond geometries of the new dihydroxy-containing mediators are tentative assignments and depicted in likely configurations based on biogenic synthesis, trapping, and labeling (see Results).

Mentions: We present a hypothetical scheme for the maresin pathway (see Fig. 5). DHA is converted to 14-hydroperoxydocosahexaenoic acid, likely via 12-LOX in humans, as shown in incubations of DHA and 12-LOX, followed by either reduction to 14S-HDHA and/or, via double dioxygenation (e.g., sequential 12-LOX–5-LOX), to generate 7S,14S-diHDHA. In 12/15-LOX–deficient mice, 14S-HDHA generation in peritonitis was reduced >95%. The key 14S-hydroperoxide intermediate is enzymatically converted to a 13(14)-epoxide–containing intermediate that is then enzymatically hydrolyzed via a carbonium cation to bioactive 7,14S-diHDHA by creating a conjugated triene within three of the six double bonds. The results from 18O isotope incorporation using H218O demonstrated that >75% of the oxygen at the carbon 7 position was derived from H2O (see Supplemental materials and methods and Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20081880/DC1) and not from molecular oxygen, as would have been the case if this carbon 7 position alcohol group was generated by double lipoxygenation mechanism (compare with reference 20). In parallel, alcohol trapping with excess acidic methanol was performed with isolated MΦs that gave the methoxy-trapping product 7-methoxy-14-hydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, identified using LC/MS/MS targeted profiling. Its MS2 spectrum showed ions consistent with acid-assisted attack at the carbon 7 position and addition of the methoxy, giving the MS2 spectrum of m/z 373 at 10.2 min (Fig. 4, inset for ion assignments; and Fig. 5). It is also possible that a methoxy addition could have occurred at the carbon 13 position that could give essentially the same ions in MS2. It is more likely that methoxy addition was at carbon 7, because it is the least sterically hindered end of the conjugated carbonium cation.


Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions.

Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, Oh SF, Spite M - J. Exp. Med. (2008)

Biosynthetic scheme proposed for MaR1 and related products. Stereochemistries and double-bond geometries of the new dihydroxy-containing mediators are tentative assignments and depicted in likely configurations based on biogenic synthesis, trapping, and labeling (see Results).
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2626672&req=5

fig5: Biosynthetic scheme proposed for MaR1 and related products. Stereochemistries and double-bond geometries of the new dihydroxy-containing mediators are tentative assignments and depicted in likely configurations based on biogenic synthesis, trapping, and labeling (see Results).
Mentions: We present a hypothetical scheme for the maresin pathway (see Fig. 5). DHA is converted to 14-hydroperoxydocosahexaenoic acid, likely via 12-LOX in humans, as shown in incubations of DHA and 12-LOX, followed by either reduction to 14S-HDHA and/or, via double dioxygenation (e.g., sequential 12-LOX–5-LOX), to generate 7S,14S-diHDHA. In 12/15-LOX–deficient mice, 14S-HDHA generation in peritonitis was reduced >95%. The key 14S-hydroperoxide intermediate is enzymatically converted to a 13(14)-epoxide–containing intermediate that is then enzymatically hydrolyzed via a carbonium cation to bioactive 7,14S-diHDHA by creating a conjugated triene within three of the six double bonds. The results from 18O isotope incorporation using H218O demonstrated that >75% of the oxygen at the carbon 7 position was derived from H2O (see Supplemental materials and methods and Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20081880/DC1) and not from molecular oxygen, as would have been the case if this carbon 7 position alcohol group was generated by double lipoxygenation mechanism (compare with reference 20). In parallel, alcohol trapping with excess acidic methanol was performed with isolated MΦs that gave the methoxy-trapping product 7-methoxy-14-hydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, identified using LC/MS/MS targeted profiling. Its MS2 spectrum showed ions consistent with acid-assisted attack at the carbon 7 position and addition of the methoxy, giving the MS2 spectrum of m/z 373 at 10.2 min (Fig. 4, inset for ion assignments; and Fig. 5). It is also possible that a methoxy addition could have occurred at the carbon 13 position that could give essentially the same ions in MS2. It is more likely that methoxy addition was at carbon 7, because it is the least sterically hindered end of the conjugated carbonium cation.

Bottom Line: Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MPhis).Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MPhi mediator in resolving inflammation (maresin), which enhances resolution.These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MPhis in tissue homeostasis, inflammation resolution, wound healing, and host defense.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. cnserhan@zeus.bwh.harvard.edu

ABSTRACT
The endogenous cellular and molecular mechanisms that control acute inflammation and its resolution are of wide interest. Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MPhis). During the resolution of mouse peritonitis, exudates accumulated both 17-hydroxydocosahexaenoic acid, a known marker of 17S-D series resolvin (Rv) and protectin biosynthesis, and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid from endogenous DHA. Addition of either DHA or 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid to activated MPhis converted these substrates to novel dihydroxy-containing products that possessed potent antiinflammatory and proresolving activity with a potency similar to resolvin E1, 5S,12R,18R-trihydroxyeicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, and protectin D1, 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MPhi mediator in resolving inflammation (maresin), which enhances resolution. These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MPhis in tissue homeostasis, inflammation resolution, wound healing, and host defense.

Show MeSH
Related in: MedlinePlus