학술논문
DEL-1 promotes macrophage efferocytosis and clearance of inflammation
Document Type
Article
Author
Kourtzelis, Ioannis; Li, Xiaofei; Mitroulis, Ioannis; Grosser, Daniel; Kajikawa, Tetsuhiro; Wang, Baomei; Grzybek, Michal; von Renesse, Janusz; Czogalla, Aleksander; Troullinaki, Maria; Ferreira, Anaisa; Doreth, Christian; Ruppova, Klara; Chen, Lan-Sun; Hosur, Kavita; Lim, Jong-Hyung; Chung, Kyoung-Jin; Grossklaus, Sylvia; Tausche, Anne Kathrin; Joosten, Leo A. B.; Moutsopoulos, Niki M.; Wielockx, Ben; Castrillo, Antonio; Korostoff, Jonathan M.; Coskun, Ünal; Hajishengallis, George; Chavakis, Triantafyllos
Source
Nature Immunology; January 2019, Vol. 20 Issue: 1 p40-49, 10p
Subject
Language
ISSN
15292908; 15292916
Abstract
Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte–endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor–dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell–derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.