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Cutting Edge: Human Vagus Produces Specialized Proresolving Mediators of Inflammation with Electrical Stimulation Reducing Proinflammatory Eicosanoids This information is current as of September 26, 2021. Charles N. Serhan, Xavier de la Rosa and Charlotte C. Jouvene J Immunol published online 24 October 2018 http://www.jimmunol.org/content/early/2018/10/23/jimmun ol.1800806 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/10/23/jimmunol.180080 Material 6.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 26, 2021 *average 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 24, 2018, doi:10.4049/jimmunol.1800806 Cutting Edge: Human Vagus Produces Specialized Proresolving Mediators of Inflammation with Electrical Stimulation Reducing Proinflammatory Eicosanoids Charles N. Serhan, Xavier de la Rosa, and Charlotte C. Jouvene Inflammatory resolution is a process that, when uncon- nuclear translocation and stimulates the JAK2/STAT3 path- trolled, impacts many organs and diseases. As an active, way to reduce cytokines (4). self-limited inflammatory process, resolution involves Mechanisms controlling the magnitude and duration of biosynthesis of specialized proresolving mediators inflammatory responses have recently attracted considerable (SPM) (e.g., lipoxins, resolvins [Rv], protectins, and attention (1, 2). Self-limited acute inflammatory responses activate biosynthesis of novel specialized proresolving medi- maresins). Because vagal stimulation impacts inflam- Downloaded from mation, we examined human and mouse vagus ex vivo ators (SPM) that stimulate resolution. SPM function by 1) to determine if they produce lipid mediators. Using limiting further neutrophil infiltration, 2) reducing collateral targeted lipid mediator metabololipidomics, we identi- tissue damage, and 3) activating macrophages to engulf apo- fied lipoxins, Rv, and protectins produced by both hu- ptotic cells and debris as well as 4) clearing microbial infec- man and mouse vagus as well as PGs and leukotrienes. tions (2). The SPM include lipoxin (LX), resolvin (Rv), Human vagus produced SPM (e.g., RvE1, NPD1/ protectin (PD), and maresin (MaR) families biosynthesized http://www.jimmunol.org/ from essential polyunsaturated fatty acids. Each SPM family PD1, MaR1, RvD5, and LXA4) on stimulation that differed from mouse (RvD3, RvD6, and RvE3), dem- member also counter-regulates cytokines, chemokines, and onstrating species-selective SPM. Electrical vagus stim- proinflammatory eicosanoids (e.g., PGF2a and leukotrienes [LT]) to reduce inflammation and activate IL-10 (2). Rv also ulation increased SPM in both human and mouse b vagus as did incubations with Escherichia coli. Electri- block macrophage NLRP3 inflammasome, reducing IL-1 cal vagus stimulation increased SPM and decreased PGs (5), and reduce pain (6, 7). Recently, new SPM structures containing peptide conjugates were elucidated that stimulate and leukotrienes. These results provide direct evidence resolution and activate tissue regeneration (8). for vagus SPM and eicosanoids. Moreover, they suggest by guest on September 26, 2021 We found that vagotomy delays resolution of inflammation that this vagus SPM circuit contributes to a new prore- (9). This delay involves shifting lipid mediators (LM) with solving vagal reflex. The Journal of Immunology, 2018, reduced Rv to proinflammatory status, demonstrating a novel 201: 000–000. vagus-resolution circuit (9, 10). During bacterial infection, vagus also controls resolution via biosynthesis of specific SPM he acute inflammatory response is critical in host that function as immunoresolvents (e.g., PD conjugate in tissue defense and, when unresolved, can lead to chronic regeneration [PCTR]1) upregulated by acetylcholine via ILC-3 T inflammation associated with many human diseases control of macrophage SPM biosynthesis and phenotype (10). (1, 2). New therapeutic approaches are needed for diseases in In view of these findings, we investigated whether vagus can which unresolved inflammation contributes to progressive loss directly produce LM. In this article, we report that human of organ function. The vagus nerve–based inflammatory reflex vagus produces specific SPM, identified using liquid chro- uncovered by Tracey and colleagues (3) regulates immune matography–tandem mass spectrometry (LC-MS/MS)–based function and inflammation. One mechanism of neural– metabololipidomics, that differed from those produced by immune control involves activation of macrophage a7 nico- mouse vagus. Escherichia coli increased LM-SPM, and elec- tinic acetylcholine receptors that inhibit proinflammatory trical vagus stimulation (EVS) ex vivo increased SPM and cytokines. This macrophage a7 receptor inhibits NF-kB reduced both PGs and LT. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthe- Medical School, Hale Building for Transformative Medicine, Suite 3-016, 60 Fenwood siology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Road, Boston, MA 02115. E-mail address: [email protected] Medical School, Boston, MA 02115 The online version of this article contains supplemental material. ORCIDs: 0000-0003-4627-8545 (C.N.S.); 0000-0003-3927-364X (X.d.l.R.); 0000- Abbreviations used in this article: CysLT, cysteinyl LT; DC, direct current; EVS, elec- 0003-3978-8096 (C.C.J.). trical vagus stimulation; LC-MS/MS, liquid chromatography–tandem mass spectrome- Received for publication June 21, 2018. Accepted for publication September 24, 2018. try; LM, lipid mediator; LT, leukotriene; LX, lipoxin; MaR, maresin; NPD1/PD1, neuroprotectin D1; PCA, principal component analysis; PCTR, PD conjugate in tissue This work was supported in part by National Institutes of Health Grant R01GM038765 regeneration; PD, protectin; PDX, 10S,17S-diHDHA; Rv, resolvin; SPM, specialized (to C.N.S.). proresolving mediator. Address correspondence and reprint requests to Prof. Charles N. Serhan, Center for Ex- perimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital/Harvard Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800806 2 CUTTING EDGE: VAGAL SPM AND EICOSANOIDS Materials and Methods acid (16). Hence, 17R-NPD1/PD1 may have resulted from Human and mouse tissues aspirin use by the organ donors. Alternately, aspirin-triggered Rv (17R epimer) and LX (15R epimer) are also produced by a Fresh human vagi (deidentified) purchased from Tissue for Research (Ellingham, Bungay, Suffolk, U.K.) were analyzed under protocol no. 1999P0001279 approved new pathway in neural tissues that uses sphingosine kinase 1 by the Partners Human Research Committee. Each postmortem, full-length to acetylate COX-2 as a mechanism to biosynthesize aspirin- human vagus was thawed on arrival, measured, dissected, and incubated triggered epimers of SPM (17). These longer-acting endoge- in PBS (with calcium and magnesium) for 20 min at 37˚C with 5% CO2 in parallel with direct EVS with 2.5 mA 18 V direct current (DC) for 20 min in nous epimers of SPM are potent proresolving agonists (2). PBS at 37˚C (ApeX Type A stimulator; ApeX Electronics, Schenectady, NY), Human vagus also produced MaR1 and its pathway marker, or coincubated with E. coli (109 CFU for 3 h at 37˚C). Deuterium-labeled 7S,14S-dihydroxy-DHA (Fig. 1). In addition to MaR1’s po- standards for SPM and eicosanoid extraction recoveries were from Cayman tent proresolving actions with human leukocytes (2, 14) and Chemical (Ann Arbor, MI). For abbreviations and stereochemical assign- ments with the full name for each of the SPM, see (11, 12). Animal exper- platelets (18), MaR1 is neuroprotective and activates recovery imental procedures were approved by the Institutional Animal Care and Use from spinal cord injury (19). Committee of Brigham and Women’s Hospital (protocol no. 2016N000145) In human vagus, SPM from arachidonic acid (i.e., LXA4 and and complied with institutional and U.S. National Institutes of Health guidelines. Six- to eight-week-old FVB male mice (Charles River Laborato- LXB4) were also identified (Fig. 1). Along with their ability to ries, Wilmington, MA) were fed ad libitum Laboratory Rodent Diet 20-5058 activate resolution (2), LXA4 reduces neuroinflammation and (Purina Mills, Great Summit, MO). neuropathic pain following hemisection of spinal cord via reducing microglial activation (20), and both LXA and LXB LM metabololipidomics 4 4 are neuroprotective (21). Thus, their production by human Downloaded from Cold methanol containing deuterium-labeled (12) internal standards vagus, as well as other SPM documented in this article from (500 pg/sample) were added to all samples. Following solid-phase extraction, LM-SPM
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