DEL-1 promotes macrophage efferocytosis and clearance of inflammation

Ioannis Kourtzelis, Xiaofei Li, Ioannis Mitroulis, Daniel Grosser, Tetsuhiro Kajikawa, Baomei Wang, Michal Grzybek, Janusz von Renesse, Aleksander Czogalla, Maria Troullinaki, Anaisa Ferreira, Christian Doreth, Klara Ruppova, Lan Sun Chen, Kavita Hosur, Jong Hyung Lim, Kyoung Jin Chung, Sylvia Grossklaus, Anne Kathrin Tausche, Leo A.B. JoostenNiki M. Moutsopoulos, Ben Wielockx, Antonio Castrillo, Jonathan M. Korostoff, Ünal Coskun, George Hajishengallis, Triantafyllos Chavakis

Research output: Contribution to journalArticlepeer-review

161 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)40-49
Number of pages10
JournalNature Immunology
Volume20
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1

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