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15-Epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-Κb

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15-Epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-Κb Published March 9, 2018, doi:10.4049/jimmunol.1602090 The Journal of Immunology 15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-kB Regulators in Bacterial Pneumonia Ho Pan Sham,*,1 Katherine H. Walker,*,1 Raja-Elie E. Abdulnour,* Nandini Krishnamoorthy,* David N. Douda,* Paul C. Norris,† Ioanna Barkas,* Sarah Benito-Figueroa,* Jennifer K. Colby,* Charles N. Serhan,† and Bruce D. Levy* Specialized proresolving mediators (SPMs) decrease NF-kB activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-kB regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A4 (15-epi-LXA4), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-kB regulators A20 and single Ig IL-1R–related molecule (SIGIRR). Of interest, 15-epi-LXA4 induced A20 and SIGIRR in an lipoxin A4 receptor/ formyl peptide receptor 2 (ALX/FPR2) receptor–dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-kB–induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA4 also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-kB activity and to establish mechanisms for NF-kB regulation by SPMs for pneumonia resolution. The Journal of Immunology, 2018, 200: 000–000. athogen-induced inflammation is a major and untreated to bacteria, including generation of proinflammatory cytokines and source of morbidity and mortality in common infections, antimicrobial peptide production (8, 9). To terminate mucosal NF- P such as pneumonia (1–3). In health, the resolution of in- kB activity, the intracellular regulatory proteins A20 (also known as flammation requires cessation of proinflammatory signaling TNF-a–induced protein 3), single Ig IL-1R–related molecule without hindering host defense (4). In response to tissue injury or (SIGIRR, also known as Toll IL-1R 8), and suppression of tumor- infection, specialized proresolving mediators (SPMs), which in- genicity 2 (ST2) are rapidly induced (10–12). The expression of clude lipoxins, resolvins, protectins, and maresins, are produced in these negative regulators for NF-kB is influenced by detection of a temporally regulated manner and can block proinflammatory bacteria or LPS (13–15); however, the endogenous braking signals responses, in part via decreasing NF-kB activity (5, 6). that induce A20 and SIGIRR have yet to be defined. by guest on September 30, 2021. Copyright 2018 Pageant Media Ltd. At the mucosal interface, airway epithelial cells play important In murine bacterial pneumonia from Escherichia coli,SPMsare roles to initiate and direct host responses against invading patho- produced in a temporally regulated manner (16, 17). The SPM gens (7). Failure to regulate NF-kB activity can lead to excessive 15-epi-lipoxin A4 (15-epi-LXA4, first defined as aspirin-triggered tissue damage. NF-kB activation in airway epithelial cells serves lipoxin A4) is a potent autacoid agonist for NF-kB inhibition, in pivotal roles during the early induction of inflammatory responses part via activation of the G-protein coupled receptor ALX/FPR2 (18, 19). Stereoisomers of SPMs, including 15-epi-LXA4,canbe synthesized in the absence of aspirin via cytochrome P450 enzymes *Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and †Center for Experimental Ther- (present in lung epithelial cells) (20). Cellular and molecular mech- apeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard anisms involved in SPM-mediated NF-kB inhibition are of interest Medical School, Boston, MA 02115 http://classic.jimmunol.org (21). In this study, we have identified 15-epi-LXA4 and select 1 H.P.S. and K.H.W. contributed equally to this work. D-series resolvins as endogenous agonists for A20 and SIGIRR ex- ORCIDs: 0000-0003-1198-8125 (K.H.W.); 0000-0003-4625-6207 (I.B.); 0000-0003- pression for inhibition of NF-kB activity in the control of pneumonia. 4627-8545 (C.N.S.). Received for publication December 12, 2016. Accepted for publication February 9, 2018. Materials and Methods This work was supported by National Institutes of Health Grants P01-GM095467 (to Materials Downloaded from B.D.L. and C.N.S.), K08-HL130540 (to R.-E.E.A.), 2T32HL007633-31 (to B.D.L. and K.H.W.), and F32 AI134019-01 (to K.H.W.), as well as a Canadian Institute of The SPM 15-epi-LXA4 was purchased from EMD Millipore (Billerica, Health Research postdoctoral fellowship (to H.P.S. and D.N.D.). MA) and Cayman Chemical (Ann Arbor, MI). Resolvin D2 (RvD2), RvD3, and 17-epi-RvD1 were validated and prepared by lipid mediator Address correspondence and reprint requests to Dr. Bruce D. Levy, Harvard Medical School, Brigham and Women’s Hospital, 60 Fenwood Road, Boston, MA 02115. metabolomic core and total organic synthesis core of P01-GM095467; E-mail address: [email protected] 17-epi-RvD1 and resolvin D3 were additionally purchased from Cayman Chemical. The online version of this article contains supplemental material. Abbreviations used in this article: BALF, bronchoalveolar lavage fluid; BPI, bactericidal Lipid mediator metabololipidomics permeability-increasing protein; 15-epi-LXA4, 15-epi-lipoxin A4; LL-37, human ortholog Lung tissue isolates were disrupted gently in methanol then processed for of cathelicidin; m, murine; mCRAMP, murine cathelicidin-related antimicrobial peptide; MOI, multiplicity of infection; p.i., postinfection; RvD2, resolvin D2; SIGIRR, single Ig liquid chromatography followed by tandem mass spectrometry (16). Levels IL-1R–related molecule; SPM, specialized proresolving mediator; ST2, suppression of of 15-epi-LXA4 were monitored and quantified by multiple reaction tumorgenicity 2; TLR4, Toll-like receptor 4; WT, wild type. monitoring developed using signature ion fragments for 15-epi-LXA4 (m/z 351/115) (22). Quantification was carried out on the basis of the area Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 beneath the peak, obtained with multiple reaction-monitoring transitions www.jimmunol.org/cgi/doi/10.4049/jimmunol.1602090 2 SPMs INDUCE NF-kB REGULATORS and linear calibration curves for synthetic and authentic standards. Deu- Quantification of neutrophil number terated standards were added to determine for recoveries (22). Following the collection of BALF and removal of the supernatant, cells were Cell culture and cell stimulation stained with CD45, CD11B, CD11C, and Ly6G (BioLegend). Neutrophils were identified as (CD45+, CD11B+, CD11C2, and Ly6G+). Cell counts Calu-3 lung cells were obtained from the American Type Culture Collection were obtained by adding a known amount of fluorescent counting beads (Manassas, VA) and grown in Eagle’s MEM (American Type Culture (CountBright; Life Technologies) to the BALF cell pellet prior to flow m Collection) with penicillin (100 U/ml), streptomycin (100 g/ml) (Life cytometry as per the manufacturer’s recommendations and normalized to Technologies, Carlsbad, CA), and 10% FBS (Denville Scientific, South lavage. FACSCanto II (BD Biosciences, San Jose, CA) and FlowJo V.10 Plainfield, NJ), and maintained at 37˚C with 5% CO2. Cells were seeded in software (Tree Star, Ashland, OR) were used for analyses. 6- or 12-well plates (Corning, Corning, NY) and used for experiments at confluence ∼4 d after seeding. Calu-3 cells were incubated in serum-free Measurement of CXCL1 levels in BALF media with penicillin and streptomycin during stimulation. Calu-3 cells were exposed to different specialized proresolving lipid mediators BALF was collected as described above. After centrifugation, cell-free (10–100 nM) for 30 min before stimulation with either LPS (10 mg/ml) supernatants were collected at specified time points and CXCL1 levels (Sigma-Aldrich, St Louis, MO) or IL-1b (1 ng/ml) (BioLegend, San were assessed using ELISA following the manufacturer’s instructions Diego, CA). Cells were harvested at the specified time points for RNA or (R&D Systems). protein extraction and Western blot analysis. Western blotting Measurement of CXCL8 Following incubation, cells were lysed in radioimmunoprecipitation assay The level of CXCL8 released into the supernatant was measured using an buffer (Boston Bio Products, Ashland, MA) with PhosSTOP and cOmplete ELISA kit (R&D Systems, Minneapolis, MN) following the manufac- Protease Inhibitor mixture (Roche Life Science, Indianapolis, IN). Cell turer’s instructions. lysates were resolved by AnyKDa SDS PAGE gel (Bio-Rad) and transferred to polyvinylidene difluoride membranes (Bio-Rad). Blots were blocked for RNA extraction and quantitative real-time PCR 1 h with 5% BSA in TBST. Membranes were incubated with primary Ab (1:1000–1:3000) in TBST overnight at 4˚C and probed with the respective Following euthanasia, mouse lungs were removed and immediately secondary Ab (1:2000) (Cell Signaling Technology, Danvers, MA) for 1 h transferred to TRIZOL (Life Technologies), frozen in liquid N2,and at room temperature. Membranes were then incubated with WesternSure stored at 280˚C. Total RNA was extracted using a chloroform extraction ECL (Li-COR Biosciences, Lincoln, NE) or Pierce ECL (Thermo Fisher method (23). cDNA was synthesized
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