1. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
2. Present addresses: Klinik und Poliklinik für Neurologie & Experimentelle Neurologie, Campus-Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany (J.M.S.); Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan (M.A.).
3. These authors contributed equally to this work.

Correspondence to: Charles N. Serhan¹ Correspondence and requests for materials should be addressed to C.N.S. (Email: cnserhan@zeus.bwh.harvard.edu).

Abstract

Resolution of acute inflammation is an active process essential for appropriate host responses, tissue protection and the return to homeostasis^{1, 2, 3}. During resolution, specific omega-3 polyunsaturated fatty-acid-derived mediators are generated within resolving exudates, including resolvin E1 (RvE1)⁴ and protectin D1 (PD1)⁵. It is thus important to pinpoint specific actions of RvE1 and PD1 in regulating tissue resolution. Here we report that RvE1 and PD1 in nanogram quantities promote phagocyte removal during acute inflammation by regulating leukocyte infiltration, increasing macrophage ingestion of apoptotic polymorphonuclear neutrophils in vivo and in vitro, and enhancing the appearance of phagocytes carrying engulfed zymosan in lymph nodes and spleen. In this tissue terrain, inhibition of either cyclooxygenase or lipoxygenases—pivotal enzymes in the temporal generation of both pro-inflammatory and pro-resolving mediators—caused a 'resolution deficit' that was rescued by RvE1, PD1 or aspirin-triggered lipoxin A₄ analogue. Also, new resolution routes were identified that involve phagocytes traversing perinodal adipose tissues and non-apoptotic polymorphonuclear neutrophils carrying engulfed zymosan to lymph nodes. Together, these results identify new active components for postexudate resolution traffic, and demonstrate that RvE1 and PD1 are potent agonists for resolution of inflamed tissues.

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