DEL-1 promotes macrophage efferocytosis and clearance of inflammation.
Ioannis KourtzelisXiaofei LiIoannis MitroulisDaniel GrosserTetsuhiro KajikawaBaomei WangMichal GrzybekJanusz von RenesseAleksander CzogallaMaria TroullinakiAnaisa FerreiraChristian DorethKlara RuppovaLan-Sun ChenKavita HosurJong-Hyung LimKyoung-Jin ChungSylvia GrossklausAnne Kathrin TauscheLeo A B JoostenNiki M MoutsopoulosBen WielockxAntonio CastrilloJonathan M KorostoffÜnal CoskunGeorge HajishengallisTriantafyllos ChavakisPublished in: Nature immunology (2018)
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.
Keyphrases
- oxidative stress
- endothelial cells
- diabetic rats
- poor prognosis
- anti inflammatory
- adipose tissue
- high glucose
- drug induced
- cell death
- single molecule
- binding protein
- peripheral blood
- stem cells
- bone marrow
- escherichia coli
- signaling pathway
- staphylococcus aureus
- long non coding rna
- small molecule
- respiratory failure
- protein protein
- solid state