{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:52:51Z","timestamp":1774965171707,"version":"3.50.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T00:00:00Z","timestamp":1564617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alternative (M2)-polarized macrophages possess high capacities to produce specialized proresolving mediators (SPM; i.e., resolvins, protectins, and maresins) that play key roles in resolution of inflammation and tissue regeneration. Vacuolar (H+)-ATPase (V-ATPase) is fundamental in inflammatory cytokine trafficking and secretion and was implicated in macrophage polarization toward the M2 phenotype, but its role in SPM production and lipid mediator biosynthesis in general is elusive. In this study, we show that V-ATPase activity is required for the induction of SPM-biosynthetic pathways in human M2-like monocyte-derived macrophages (MDM) and consequently for resolution of inflammation. Blockade of V-ATPase by archazolid during IL-4\u2013induced human M2 polarization abrogated 15-lipoxygenase-1 expression and prevented the related biosynthesis of SPM in response to pathogenic Escherichia coli, assessed by targeted liquid chromatography\u2013tandem mass spectrometry\u2013based metabololipidomics. In classically activated proinflammatory M1-like MDM, however, the biosynthetic machinery for lipid mediator formation was independent of V-ATPase activity. Targeting V-ATPase in M2 influenced neither IL-4\u2013triggered JAK\/STAT6 nor the mTOR complex 1 signaling but strongly suppressed the ERK-1\/2 pathway. Accordingly, the ERK-1\/2 pathway contributes to 15-lipoxygenase-1 expression and SPM formation in M2-like MDM. Targeting V-ATPase in vivo delayed resolution of zymosan-induced murine peritonitis accompanied by decreased SPM levels without affecting proinflammatory leukotrienes or PGs. Together, our data propose that V-ATPase regulates 15-lipoxygenase-1 expression and consequent SPM biosynthesis involving ERK-1\/2 during M2 polarization, implying a crucial role for V-ATPase in the resolution of inflammation.<\/jats:p>","DOI":"10.4049\/jimmunol.1900236","type":"journal-article","created":{"date-parts":[[2019,7,12]],"date-time":"2019-07-12T20:25:17Z","timestamp":1562963117000},"page":"1031-1043","source":"Crossref","is-referenced-by-count":32,"title":["Vacuolar (H+)-ATPase Critically Regulates Specialized Proresolving Mediator Pathways in Human M2-like Monocyte-Derived Macrophages and Has a Crucial Role in Resolution of Inflammation"],"prefix":"10.1093","volume":"203","author":[{"given":"Zhigang","family":"Rao","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical\/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Pace","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical\/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul M","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical\/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossella","family":"Bilancia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II , 80131 Naples ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabiana","family":"Troisi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical\/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedemann","family":"B\u00f6rner","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical\/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4591-7037","authenticated-orcid":false,"given":"Nico","family":"Andreas","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Jena University Hospital , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8443-5893","authenticated-orcid":false,"given":"Thomas","family":"Kamradt","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Jena University Hospital , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Menche","sequence":"additional","affiliation":[{"name":"Kekul\u00e9-Institut f\u00fcr Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universit\u00e4t Bonn , D-53121 Bonn ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonietta","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II , 80131 Naples ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4627-8545","authenticated-orcid":false,"given":"Charles N","family":"Serhan","sequence":"additional","affiliation":[{"name":"Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Gerstmeier","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical\/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Werz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical\/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena , 07743 Jena ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,8,15]]},"reference":[{"key":"2025030417540892100_r1","doi-asserted-by":"crossref","DOI":"10.1128\/microbiolspec.MCHD-0001-2014","article-title":"Macrophage proresolving mediators-the when and where","volume":"4","author":"Dalli","year":"2016","journal-title":"Microbiol. 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