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Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation Hildur H

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Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation Hildur H Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation Hildur H. Arnardottir, Jesmond Dalli, Lucy V. Norling, Romain A. Colas, Mauro Perretti and Charles N. Serhan This information is current as of September 27, 2021. J Immunol published online 17 August 2016 http://www.jimmunol.org/content/early/2016/08/17/jimmun ol.1502268 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/08/17/jimmunol.150226 Material 8.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 17, 2016, doi:10.4049/jimmunol.1502268 The Journal of Immunology Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation Hildur H. Arnardottir,* Jesmond Dalli,*,1 Lucy V. Norling,† Romain A. Colas,*,1 Mauro Perretti,† and Charles N. Serhan* Uncontrolled inflammation is a unifying component of many chronic inflammatory diseases, such as arthritis. Resolvins (Rvs) are a new family from the endogenous specialized proresolving mediators (SPMs) that actively stimulate resolution of inflam- mation. In this study, using lipid mediator metabololipidomics with murine joints we found a temporal regulation of endog- enous SPMs during self-resolving inflammatory arthritis. The SPMs present in self-resolving arthritic joints include the D-series Rvs, for example, RvD1, RvD2, RvD3, and RvD4. Of note, RvD3 levels were reduced in inflamed joints from mice with delayed-resolving arthritis when compared with self-resolving inflammatory arthritis. RvD3 was also reduced in serum from rheumatoid arthritis patients compared with healthy controls. RvD3 administration reduced joint leukocytes as well as Downloaded from paw joint eicosanoids, clinical scores, and edema. Taken together, these findings provide evidence for dysregulated endogenous RvD3 levels in inflamed paw joints and its potent actions in reducing murine arthritis. The Journal of Immunology, 2016, 197: 000–000. cute inflammation is a host-protective response against mediators (e.g., leukotrienes [LTs], PGs, and cytokines) (1), which injury or infection that when uncontrolled can lead to mount the initiation and propagation of the initial acute inflam- http://www.jimmunol.org/ A chronic inflammation, scarring, and eventual loss of matory response (3, 4). This novel genus of bioactive lipid me- tissue function (1, 2). The ideal outcome of acute inflammation is diators (LMs) biosynthesized from essential fatty acids (EFAs) in complete resolution, an active process now known to be orches- resolving inflammatory exudates, includes lipoxins (LXs), resol- trated by specialized proresolving mediators (SPMs) that limit fur- vins (Rvs), protectins (PDs), and maresins (MaRs) (1, 5). They ther neutrophil recruitment and counterregulate proinflammatory actively promote catabasis via potent anti-inflammatory and pro- resolving actions (e.g., stimulating leukocyte uptake of apoptotic cells [efferocytosis] and bacterial clearance [reviewed in Ref. 1]), *Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, providing a molecular basis for novel therapeutic approaches via Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; promoting resolution (1). by guest on September 27, 2021 † and William Harvey Research Institute, Barts and London School of Medicine, Arthritis is a significant clinical problem characterized by ex- Queen Mary University of London, London EC1M 6BQ, United Kingdom uberant inflammation leading to joint destruction and pain (6, 7). 1Current address: William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, U.K. Emerging evidence indicates that failure to engage proresolving ORCIDs: 0000-0002-5163-3946 (H.H.A.); 0000-0001-6328-3640 (J.D.); 0000-0001- pathways may contribute to persistent chronic inflammation, such 5316-9115 (L.V.N.); 0000-0003-2068-3331 (M.P.); 0000-0003-4627-8545 (C.N.S.). as in rheumatoid arthritis (RA) (1, 2). Current therapeutic ap- Received for publication October 21, 2015. Accepted for publication July 12, 2016. proaches aim to disrupt the inflammatory response, slow disease This work was supported in part by National Institutes of Health Grants P01GM095467 progression, and limit pain (2, 8). These include methotrexate, and R01GM38765 (to C.N.S.), a postdoctoral fellowship from the Arthritis Foundation anti-TNF biologics, and nonsteroidal anti-inflammatory drugs (8). (to H.H.A.), and by Arthritis Research UK Carrier Development Fellowship 19909 (to However, these treatments may have drawbacks in terms of in- L.V.N.). J.D. is funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and Royal Society Grant 107613/Z/15/Z. fections and may prevent resolution and tissue repair (1, 8, 9). Address correspondence and reprint requests to Dr. Charles N. Serhan, Center for Hence, safe and effective treatments that can regulate arthritic Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital inflammation are still in need. In that context, 17R-RvD1 (7S,8R,17R- and Harvard Medical School, 77 Avenue Louis Pasteur, HIM 829, Boston, MA trihydroxy-docosa-4Z,9E,11E,13Z,15E,19Z-hexaenoic acid) and the 02115. E-mail address: [email protected] D-series Rv pathway marker 17R-hydroxydocosahexaenoic acid The online version of this article contains supplemental material. (17R-HDHA) are log order more potent than opioids, cyclooxy- Abbreviations used in this article: CHO, Chinese hamster ovary; DHA, docosahexaenoic acid; EFA, essential fatty acid; KO, knockout; LC-MS/MS, liquid chromatography– genase inhibitors, or glucocorticoids in modulating inflammatory tandem mass spectrometry; LM, lipid mediator; LT, leukotriene; LTB4, leukotriene B4 pain in a preclinical model of arthritis in rats (10). (5S,12R-dihydroxy-eicosa-6Z,8E,10E,14Z-tetraenoic acid); LX, lipoxin; LXA4, lipoxin Resolvins of the D-series are enzymatically biosynthesized from A4 (5S,6R,15S-trihydroxy-eicosa-7E,9E,11Z,13E-tetraenoic acid); MaR, maresin; MaR1, maresin 1 (7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid); the omega-3 EFA, docosahexaenoic acid (DHA), including RvD1, a MS/MS, tandem mass spectrometry; PD, protectin; PGD2, 11-oxo-9 ,15S-dihydroxy- RvD2 (7S,16R,17S-trihydroxy-docosa-4Z,8E,10Z,12E,14E,19Z- a prosta-5Z,13E-dien-1-oic acid; PGE2, 9-oxo-11 ,15S-dihydroxy-prosta-5Z,13E-dien-1- hexaenoic acid), RvD3 (4S,11R,17S-trihydroxy-docosa-5Z,7E,9E, oic acid; PLS-DA, partial least-squares discriminant analysis; RA, rheumatoid arthritis; 17R-HDHA, 17R-hydroxydocosahexaenoic acid; Ri, resolution interval; Rv, resolvin; RvD1, 13Z,15E,19Z-hexaenoic acid), and RvD4 (4S,5R,17S-trihydroxy- resolvin D1 (7S,8R,17S-trihydroxy-docosa-4Z,9E,11E,13Z,15E,19Z-hexaenoic acid); RvD2, docosa-6E,8E,10Z,13Z,15E,19Z-hexaenoic acid) (1). Recently, we resolvin D2 (7S,16R,17S-trihydroxy-docosa-4Z,8E,10Z,12E,14E,19Z-hexaenoic acid); RvD3, resolvin D3 (4S,11R,17S-trihydroxy-docosa-5Z,7E,9E,13Z,15E,19Z-hexaenoic acid); completed the stereochemistry of RvD3, having established its po- RvD4, resolvin D4 (4S,5R,17S-trihydroxy-docosa-6E,8E,10Z,13Z,15E,19Z-hexaenoic tent proresolving actions and unique temporal profile late within a acid); SPM, specialized proresolving mediator; TxB2,thromboxaneB2 (9 ,11,15S- the resolution phase (11), suggesting it may have a specific role trihydroxy-thromba-5Z,13E-dien-1-oic acid); VIP, variable influence on projection. in regulating resolution. Given these properties, we investigated Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 the role and action of RvD3 in arthritis. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502268 2 RvD3 AND ARTHRITIS Materials and Methods K/BxN serum transfer inflammatory arthritis model Animals For self-resolving and delayed-resolving arthritis, C57BL/6 male mice were m Male C57BL/6 mice (8 wk old) were obtained from Charles River Labo- administered arthritogenic K/BxN serum (100 l, i.p.) at days 0 and 2 for ratories (Newton, MA). All animal experiments were in accordance with the self-resolving arthritis, and with additional challenge on day 8 for delayed- Harvard Medical Area Standing Committee on Animals (protocol no. 02570). resolving arthritis. Clinical scores were assessed (score criteria per paw: 0, For some experiments, male C57BL/6 mice (12 wk old) were obtained from no signs of inflammation; 1, inflammation in one of the following aspects— Charles River UK (Kent, U.K.) or ALX/fpr2/3 knockout (KO) mice were individual phalange joints, localized wrist/ankle, or swelling on surface of generated on a C57BL/6 background (and backbackcrossed
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