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Proresolving Mediators Resolution in the Mucosa Antimicrobial Aspects of Inflammatory Resolution in the Mucosa: A Role for Proresolving Mediators This information is current as Eric L. Campbell, Charles N. Serhan and Sean P. Colgan of September 28, 2021. J Immunol 2011; 187:3475-3481; ; doi: 10.4049/jimmunol.1100150 http://www.jimmunol.org/content/187/7/3475 Downloaded from References This article cites 85 articles, 36 of which you can access for free at: http://www.jimmunol.org/content/187/7/3475.full#ref-list-1 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 28, 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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Antimicrobial Aspects of Inflammatory Resolution in the Mucosa: A Role for Proresolving Mediators Eric L. Campbell,* Charles N. Serhan,† and Sean P. Colgan* Mucosal surfaces function as selectively permeable bar- what endogenous mechanisms control the magnitude and riers between the host and the outside world. Given duration of the acute response, particularly as they relate to their close proximity to microbial Ags, mucosal surfaces the cardinal signs of inflammation (2, 4). It has now become have evolved sophisticated mechanisms for maintaining evident that the resolution program of acute inflammation homeostasis and preventing excessive acute inflamma- particularly within mucosal surfaces remains to be uncovered, tory reactions. The role attributed to epithelial cells and that a complete understanding of these critical pathways was historically limited to serving as a selective barrier; will undoubtedly direct new therapeutic opportunities. in recent years, numerous findings implicate an active Inflammation at mucosal surfaces provides a unique setting Downloaded from role of the epithelium with proresolving mediators in for which to define resolution pathways. By their nature, mu- the maintenance of immunological equilibrium. In this cosal surfaces interact with the environment and thereby the brief review, we highlight new evidence that the epithe- microbial world in which we live. Important in this regard, the microbiota of each mucosal surface is unique. It is estimated, lium actively contributes to coordination and resolution for example, that the skin harbors 182 different bacterial of inflammation, principally through the generation of species, whereas the large intestine may support as many as http://www.jimmunol.org/ anti-inflammatory and proresolution lipid mediators. v v 1220 different bacterial phylotypes (5). Given this diversity These autacoids, derived from -6 and -3 polyunsat- of microbiota, it is not surprising that humans have evolved urated fatty acids, are implicated in the initiation, pro- unique mechanisms to counteract regular microbial chal- gression, and resolution of acute inflammation and lenges. Along these same lines, the timely resolution of on- display specific, epithelial-directed actions focused going local inflammation has evolved to these ever-changing on mucosal homeostasis. We also summarize present challenges. We are only now beginning to appreciate the unique knowledge of mechanisms for resolution via regulation features and importance of these responses. of epithelial-derived antimicrobial peptides in response In this brief review, we highlight recent discoveries that by guest on September 28, 2021 to proresolving lipid mediators. The Journal of impact the active resolution of mucosal inflammation. Given Immunology, 2011, 187: 3475–3481. their founding role in activeresolutionmechanisms,we have focused on the unique contributions of specialized proresolving mediators (SPMs), namely, the resolvins, lipid- he resolution of ongoing inflammation was histori- derived mediators that are agonist dependent, temporally cally considered a passive act of the healing process distinct, and functionally carry novel potent mucosa-directed T with dilution of proinflammatory chemical mediators signals (2). (1) and occurred independent of active biochemical pathways (1, 2). This view has changed in fundamental ways in the past Resolution-based pharmacology: a lesson from aspirin decade. It is now appreciated that uncontrolled inflammation Resolution of inflammation and return to tissue homeostasis is a unifying component in many diseases, and new evidence is an exceptionally well-coordinated process. SPMs generated indicates that inflammatory resolution is a biosynthetically during the resolution phase of ongoing inflammation acti- active process (3). These new findings implicate a tissue de- vely stimulate restoration of tissue homeostasis (3). The first cision process wherein acute inflammation, chronic inflam- resolvin, known today as resolvin E1 (RvE1), was identified in mation, or inflammatory resolution hold the answers as to 1999 as a potent and active initiator of resolution (4). In- *Mucosal Inflammation Program, Department of Medicine, University of Colorado Address correspondence and reprint requests to Dr. Eric L. Campbell, Mucosal Inflam- School of Medicine, Aurora, CO 80045; and †Department of Anesthesiology, Perioper- mation Program, University of Colorado Denver, Mail Stop B-146, 12700 East 19th ative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Avenue, Aurora, CO 80045. E-mail address: [email protected] Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 Abbreviations used in this article: AA, arachidonic acid; ALPI, intestinal alkaline phos- Received for publication May 20, 2011. Accepted for publication July 15, 2011. phatase; ASA, acetylsalicylic acid; ATL, aspirin-triggered lipoxin; BPI, bactericidal permeability-increasing protein; COX, cyclooxygenase; DHA, docosahexaenoic acid; E.L.C. is supported by a fellowship from the Crohn’s and Colitis Foundation of Amer- EPA, eicosapentaenoic acid; LXA , lipoxin A (5S,6R,15S-trihydroxytrihydroxy-7E, ica. The S.P.C. laboratory is supported by National Institutes of Health Grants 4 4 9E,11Z,13E-eicosatetraenoic acid); PMN, polymorphonuclear leukocyte, neutrophil; R37DK50189 and RO1HL60569. The C.N.S. laboratory is supported by National PUFA, polyunsaturated fatty acid; RvD1, resolvin D1; RvE1, resolvin E1 (5S,6R,15S- Institutes of Health Grants R01GM038765 and R01DE019938. trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid); SPM, specialized proresolving mediator. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 and Kidney Diseases; the National Institute of General Medical Sciences; the National Heart, Lung, and Blood Institute; the National Institute of Dental and Craniofacial Research; or the National Institutes of Health. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1100150 3476 BRIEF REVIEWS: ANTIMICROBIALS AND INFLAMMATORY RESOLUTION ordinate, unrestricted, acute inflammation is now acknowl- edged as an instigating factor, which, when unchecked, con- tributes to numerous chronic disease states, including cardio- vascular disease, metabolic disorders, and cancer. As such, an understanding of the pharmacology of anti-inflammation and endogenous proresolution has been a significant ven- ture (2). As a basic feature, cyclooxygenase-2 (COX-2) contributes fundamentally to both inflammation and resolution (6, 7). COX-2 expression is rapidly induced at sites of inflammation and is a key enzyme in the generation of PGs, via its oxy- genase and peroxidase activities (7). In brief, after liberation of the v-6 fatty acid arachidonic acid (AA) from cell mem- branes via phospholipase A2, the oxygenase function of COX-2 catalyzes AA to PGG2 and subsequently to PGH2 via the peroxidase activity of the enzyme. Nonsteroidal anti- inflammatory drugs lower the amplitude of inflammation and delay resolution (6, 8). Acetylsalicylic acid (ASA, aspirin), Downloaded from stands apart in that it inhibits proinflammatory signals and accelerates resolution (9). ASA irreversibly acetylates COX-2 on serine 516, rendering it incapable of converting AA to PGG2. In its acetylated state, ASA produces 15R-H(P)ETE and its peroxidase activity remains intact, resulting in for- mation of 15R-hydroxyeicosatetraenoate. Aside from ASA’s http://www.jimmunol.org/ anti-inflammatory action of inhibiting PG synthesis, 15R- hydroxyeicosatetraenoate is a precursor for proresolution 15- epi-lipoxins (10). Such aspirin-triggered lipoxins (ATLs) are FIGURE 1. “Class switching” in the lipid metabolome promotes reso- more resistant to metabolic inactivation than lipoxins (11) lution. Enzymes COX-1 and COX-2 convert AA to PGG2 by cyclo- oxygenation, and subsequently to PGH2 by peroxidation. In turn, PGH2 is and also assert anti-inflammatory and proresolving activities metabolized to PGs
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