DEL-1 Promotes Macrophage Efferocytosis and Inflammation Resolution in Periodontitis

Objectives: DEL-1 inhibits inflammatory cell recruitment and protects against interleukin-17 (IL-17)-driven inflammatory pathologies, including periodontitis. The pro-resolving lipid mediator resolvin D1 (RvD1) promotes the expression of DEL-1 and, moreover, depends on DEL-1 to mediate protection in inflammatory bone loss. These observations prompted us to investigate whether and how DEL-1 contributes to inflammation resolution.
Methods: DEL-1 concentration in the gingival crevicular fluid (GCF) of periodontitis patients before and after periodontal treatment (scaling and root planing) were determined by ELISA. Ligature-induced periodontitis and acute monosodium urate (MSU) crystal-induced peritonitis models were engaged to study the role of DEL-1 in inflammation resolution. Quantitative real-time PCR and ELISA, respectively, were used to measure the levels of DEL-1 mRNA and protein in mouse gingival tissues or peritoneal exudates. Mouse bone marrow-derived macrophages or human monocyte-derived macrophages were used to study the effect of DEL-1 on efferocytosis. Mice lacking DEL-1 (Del1^KO), b3 integrin (Itgb3^KO) or liver X receptor (Lxr^KO) were used to determine the mechanisms of DEL-1 involvement in resolution. Mice overexpressing DEL-1 specifically in the endothelium (EC-Del1) or in macrophages (CD68-Del1) were used to identify the cellular source of DEL-1 that promotes resolution.
Results: In human and mouse periodontitis, resolution of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis or acute MSU-induced inflammation failed in Del1^KO mice. DEL-1 promoted the clearance of apoptotic neutrophils (efferocytosis) by macrophages in a b3 integrin-dependent manner and induced LXR-dependent macrophage reprogramming to a pro-resolving phenotype. 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.
Conclusions: DEL-1 regulates both the initiation and resolution of inflammation. The latter activity involves the ability of DEL-1 to promote efferocytosis and macrophage reprogramming to a pro-resolving phenotype, required for successful resolution of inflammation.