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Maresin Conjugates in Tissue Regeneration Biosynthesis Enzymes in Human Macrophages

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Maresin Conjugates in Tissue Regeneration Biosynthesis Enzymes in Human Macrophages Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages Jesmond Dallia,b, Iliyan Vlasakova, Ian R. Rileya, Ana R. Rodriguezc, Bernd W. Spurc, Nicos A. Petasisd, Nan Chianga, and Charles N. Serhana,1 aCenter for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; bLipid Mediator Unit, Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London E1 2AT, United Kingdom; cDepartment of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084; and dDepartment of Chemistry, Loker Hydrocarbon Institute, University of Southern California, Los Angeles, CA 90089 Edited by Edward A. Dennis, University of California, San Diego, La Jolla, CA, and accepted by Editorial Board Member Ruslan Medzhitov August 22, 2016 (received for review May 2, 2016) Macrophages are central in coordinating immune responses, tissue activated cells display higher levels of proresolving mediators (6, repair, and regeneration, with different subtypes being associated 13). Recently, we reported that macrophages produce a family of with inflammation-initiating and proresolving actions. We recently bioactive peptide-conjugated mediators coined maresin conju- identified a family of macrophage-derived proresolving and tissue gates in tissue regeneration (MCTR) (4) and the complete ste- regenerative molecules coined maresin conjugates in tissue regener- reochemistries of MCTR1 (13R-glutathionyl, 14S-hydroxy- ation (MCTR). Herein, using lipid mediator profiling we identified 4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) [International MCTR in human serum, lymph nodes, and plasma and investigated Union of Pure and Applied Chemistry nomenclature: MCTR biosynthetic pathways in human macrophages. With human (4Z,7Z,9E,11E,13R,14S,16Z,19Z)-13-(((R)-2-amino-3-((carboxy- recombinant enzymes, primary cells, and enantiomerically pure com- methyl)amino)-3-oxopropyl)thio)-14-hydroxydocosa-4,7,9,11,16,19- pounds we found that the synthetic maresin epoxide intermediate hexaenoic acid], MCTR2 (13R-cysteinylglycinyl, 14S-hydroxy- 13S,14S-eMaR (13S,14S-epoxy- 4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic 4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid), and acid) was converted to MCTR1 (13R-glutathionyl, 14S-hydroxy- MCTR3 (13R-cysteinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z, 4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) by LTC4Sand 19Z-docosahexaenoic acid) were established (14). Each displays GSTM4. Incubation of human macrophages with LTC S inhibitors 4 potent bioactions in stimulating human phagocyte functions, blocked LTC and increased resolvins and lipoxins. The conver- 4 promotes the resolution of bacterial infections, counterregulates sion of MCTR1 to MCTR2 (13R-cysteinylglycinyl, 14S-hydroxy- the production of proinflammatory mediators, and promotes tis- 4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) was catalyzed by γ-glutamyl transferase (GGT) in human macrophages. Biosynthe- sue repair and regeneration (14). sis of MCTR3 was mediated by dipeptidases that cleaved the In the proposed MCTR biosynthetic pathway (4), human mac- cysteinyl-glycinyl bond of MCTR2 to give 13R-cysteinyl, 14S-hydroxy- rophage 12-lipoxygenase is the initiating enzyme, converting doco- 4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid. Of note, both sahexaenoic acid to 14S-hydro(peroxy)-4Z,7Z,10Z,12E,16Z,19Z- GSTM4 and GGT enzymes displayed higher affinity to 13S,14S-eMaR docosahexaenoic acid and then to 13S,14S-epoxy-4Z,7Z,9E, and MCTR1 compared with their classic substrates in the cysteinyl 11E,16Z,19Z-docosahexaenoic acid (13S,14S-eMaR). The ep- leukotriene metabolome. Together these results establish the MCTR oxide intermediate is then enzymatically converted to MCTRs. biosynthetic pathway and provide mechanisms in tissue repair and regeneration. Significance proresolving mediators | inflammation | omega-3 fatty acids | We recently uncovered a family of macrophage-derived mole- regeneration | eicosanoids cules, coined maresin conjugates in tissue regeneration, that regulate the system’s ability to clear bacteria as well as repair esolution of acute inflammation is an orchestrated host re- and regenerate damaged tissues. In the present study, we Rsponse to injury and/or infection that leads to the clearance of identified enzymes involved in the formation of these potent bacteria and tissue debris as well as tissue repair and regeneration molecules in human macrophages. These enzymes were shared (1–3). Central to the regulation of resolution responses is a novel with the classic cysteinyl leukotrienes, underscoring the pres- genus of endogenous mediators termed specialized proresolving ence of conserved biosynthetic motifs in these two functionally mediators (SPM) (2). They actively counterregulate production of distinct lipid mediator families. Inhibition of these pathways inflammation-initiating signals including cytokines, chemokines, upregulated the formation of several specialized proresolving and lipid mediators and regulate leukocyte trafficking and phe- mediator (SPM) families including D- and E-series resolvins. Thus, notype as well as promote tissue repair and regeneration (1, 2, these illustrate the dynamic nature of the SPM biosynthetic 4–6). At the site of inflammation leukocytes are key in the pro- pathways and provide new targets in the resolution of in- duction of both inflammation-initiating (7, 8) and proresolving flammation and regulation of tissue repair and regeneration. mediators (2, 4) because they carry the necessary enzymatic ma- chinery for the stereoselective conversion of precursor essential Author contributions: J.D. and C.N.S. designed research; J.D., I.V., I.R.R., and N.C. performed research; A.R.R., B.W.S., and N.A.P. contributed new reagents/analytic tools; J.D., and C.N.S. fatty acids to the bioactive mediators. conceived the overall research plan and experimental design; A.R.R., B.W.S., and N.A.P. Macrophages are central players in the acute inflammatory prepared synthetic mediators and intermediates; J.D., I.V., I.R.R., and N.C. analyzed data; response governing both initiation and resolution phases (3, 4, and J.D., I.V., and C.N.S. wrote the paper. 9–12). Distinct macrophage subtypes are involved in the reg- The authors declare no conflict of interest. ulation of these different phases of acute inflammatory re- This article is a PNAS Direct Submission. E.A.D. is a Guest Editor invited by the Editorial sponses, with macrophages from the resolution phase expressing Board. higher levels of SPM biosynthetic enzymes (12). Recent evidence Freely available online through the PNAS open access option. also demonstrates that lipid mediator profiles change with mac- 1To whom correspondence should be addressed. Email: [email protected]. rophage phenotype. Classic macrophages express higher levels This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of inflammation-initiating eicosanoids, whereas alternatively 1073/pnas.1607003113/-/DCSupplemental. 12232–12237 | PNAS | October 25, 2016 | vol. 113 | no. 43 www.pnas.org/cgi/doi/10.1073/pnas.1607003113 Downloaded by guest on September 29, 2021 AB were identified in all three human tissues, whereas MCTR2 was MCTR1 650 present in human lymph nodes and serum. Each of these molecules 100 100 LTC4 +2H was identified in accordance with published criteria (4, 14), including 521 191 matching retention times and MS-MS spectra (Fig. 1). We then assessed their amounts in relation to other peptide-conjugated lipid 308 +H205 343 mediators, namely the cysteinyl leukotrienes (7) and protectin con- +H 235 jugates in tissue regeneration (PCTR) (6). MCTR levels in human 173 217 308 Relative Intensity (%) 632 serum and plasma demonstrated that serum contained significantly 205 503 147191 325 418 521575 higher levels of MCTR1 and MCTR2 (Fig. 1, Fig. S1,andTable1). 0 100 200 300 400 500 600 In addition, levels for MCTR1, MCTR2, and MCTR3 in each of 100 MCTR2 521 LTE these tissues were comparable to those of the potent inflammation- 4 131 LTD4 -H initiating cysteinyl leukotrienes and the proresolving and tissue- 145 191 343 regenerative PCTR (Table 1). 0 235+H 100 Role of Human Macrophage LTC4S and GSTM4 in MCTR Formation. 187 GST enzymes catalyze the formation of bioactive lipid mediators 173191 503 Relative Intensity (%) 131 235 that are peptide-lipid conjugates (7, 8). The proposed homolog of Relative Abundance (%) 145 217 325 0 100 200 300 400 500 human GSTM4 in planaria promotes formation of MCTR in 464 100 MCTR3 planaria (4). Therefore, we investigated the expression of both 191 GSTM4 and LTC4S in human macrophages. Using flow cytometry MCTR1 and fluorescently conjugated antibodies, we found that human MCTR3 +H 205 macrophages expressed both LTC4S and GSTM4 (Fig. 2A). We +H next tested whether these enzymes were involved in MCTR bio- MCTR2 235 synthesis. To this end, human macrophages were transfected with 217 446 shRNA targeting LTC4S or GSTM4 or a control sequence. In cells Relative Intensity (%) 187 191 transfected with the shRNA to LTC4S or GSTM4, we found 161 235 0 > 0 2 4 6 8 10 12 14 16 18 20 22 100 150 200 250 300 350 400 450 500 50% reduction in the expression of these enzymes compared Time (min) m/z, Da with control scrambled (CS) shRNA (n= 4 independent experi- ments). We next investigated MCTR production in these cells, Fig. 1. MCTRs are
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