Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance

Winkler, Jeremy W.; Orr, Sarah; Dalli, Jesmond; Cheng, Chien-Yee C.; Sanger, Julia M.; Chiang, Nan; Petasis, Nicos A.; Serhan, Charles N.

doi:10.1038/srep18972

Cited by 91 publications

(88 citation statements)

References 25 publications

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“…Specifically, RvD1, RvD2, PD1, and 17 R -RvD1 were identified in human plasma (38) before it was possible to identify RvD4 with a matched synthetic standard (48). Thus, in view of the present results indicating that coagulation produces the SPM cluster (RvE1, RvD1, RvD5, LXB 4 , and MaR1), this did not appear to involve increases in the amounts of PD1, MaR2, RvD2, RvE2, or RvE3.…”

Section: Discussionmentioning

confidence: 99%

A cluster of immunoresolvents links coagulation to innate host defense in human blood

et al. 2017

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Blood coagulation is a protective response that prevents excessive bleeding upon blood vessel injury. Here, we investigated the relationship between coagulation and the resolution of inflammation and infection by lipid mediators (LMs) through metabololipidomic-based profiling of human whole blood (WB) during coagulation. We identified temporal clusters of endogenously produced pro-thrombotic and proinflammatory LMs (eicosanoids), as well as specialized proresolving mediators (SPMs). In addition to eicosanoids, a specific SPM cluster was identified that consisted of resolvin E1 (RvE1), RvD1, RvD5, lipoxin B4, and maresin 1, each of which was present at bioactive concentrations (0.1 to 1 nM). Removal of adenosine from the coagulating blood markedly enhanced the amounts of SPMs produced and further increased the biosynthesis of RvD3, RvD4, and RvD6. The cyclooxygenase inhibitors celecoxib and indomethacin, which block the production of thomboxanes and prostanoids, did not block the production of clot-driven SPMs. Unbiased mass cytometry analysis demonstrated that the SPM cluster produced in human blood targeted leukocytes at the single-cell level, directly activating ERK and CREB signaling in neutrophils and CD14+ monocytes. Treatment of human whole blood with the components of this SPM cluster enhanced both the phagocytosis and killing of Escherichia coli by leukocytes. Together, these data identify a pro-resolving LM circuit, including endogenous molecular brakes and accelerators, which promoted host defense. These temporal LM-SPM clusters can provide accessible metabolomic profiles for precision and personalized medicine.

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Section: Discussionmentioning

confidence: 99%

A cluster of immunoresolvents links coagulation to innate host defense in human blood

et al. 2017

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“…RvD3 was prepared and qualified by LC-MS-MS and spectroscopic analysis as in (11) and second synthetic RvD3 was obtained from Cayman Chemicals (Ann Arbor, MI). Also, the complete stereochemistry of RvD4 was recently determined (14). Multiple reaction monitoring (MRM) with signature ion pairs, Q1 (parent ion) - Q3 (characteristic daughter ion) for each molecule.…”

Section: Methodsmentioning

confidence: 99%

Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation

Arnardottir

Dalli

Norling

et al. 2016

The Journal of Immunology

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117

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Uncontrolled inflammation is a unifying component of many chronic inflammatory diseases, such as arthritis. Resolvins (Rv) are a new family from the endogenous specialized pro-resolving lipid mediators (SPM) that actively stimulate resolution of inflammation. Herein, using lipid mediator (LM) metabololipidomics with murine joints we found a temporal regulation of endogenous SPM during self-resolving inflammatory arthritis. The SPMs present in self-resolving arthritic joints include the D-series resolvins, e.g. Resolvin (Rv) D1, RvD2, RvD3 and RvD4. Of note, RvD3 levels were reduced in inflamed joints from mice with delayed-resolving arthritis when compared to self-resolving inflammatory arthritis. RvD3 was also reduced in serum from rheumatoid arthritis (RA) patients compared to healthy controls. RvD3 administration reduced joint leukocytes as well as paw joint eicosanoids, clinical scores and edema. Together, these findings provide evidence for dysregulated endogenous RvD3 levels in inflamed paw joints and its potent actions in reducing murine arthritis.

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“…See refs. (Serhan and Petasis, 2011; Winkler et al, 2016; Aursnes et al, 2015; Tungen et al, 2014; Dalli et al, 2016b) for original reports, total organic synthesis and stereochemical assignments and the text for further details.…”

Section: Figurementioning

confidence: 99%

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors

Chiang

Serhan

2017

Molecular Aspects of Medicine

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284

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The acute inflammatory response is host protective to contain foreign invaders. Many of today’s pharmacopeia that block pro-inflammatory chemical mediators can cause serious unwanted side effects such as immune suppression. Uncontrolled inflammation is now considered a pathophysiologic basis associated with, many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity and asthma, as well as the classic inflammatory diseases, e.g. arthritis, periodontal diseases. The inflammatory response is designated to be a self-limited process that produces a superfamily of chemical mediators that stimulate resolution of inflammatory responses. Specialized proresolving mediators (SPM) uncovered in recent years are endogenous mediators that include omega-3-derived families resolvins, protectins and maresins, as well as arachidonic acid-derived (n-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via novel mechanisms. Here, we review recent evidence from human and preclinical animal studies, together with the structural and functional elucidation of SPM indicating the SPM as physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. These results suggest that it is time to develop immunoresolvents as agonists for testing resolution pharmacology in nutrition and health as well as in human diseases and during surgery.

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Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance

Cited by 91 publications

References 25 publications

A cluster of immunoresolvents links coagulation to innate host defense in human blood

A cluster of immunoresolvents links coagulation to innate host defense in human blood

Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors

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