DEL-1-Regulated Immune Plasticity and Inflammatory Disorders

Abstract

In contrast to traditional immune cell-centered viewpoints, recent studies suggest that tissues are not passive recipients of immunity but have a 'regulatory say' over the host inflammatory response. Identification of tissue-derived homeostatic molecules regulating immune plasticity is seminal for understanding the inherent regulatory potential of different organs in the immune response. DEL-1 (developmental endothelial locus-1) is a secreted multidomain protein interacting with integrins and phospholipids and regulates, depending on its expression location, distinct stages of the host inflammatory response (from myelopoiesis over leukocyte recruitment to efferocytosis and resolution of inflammation). Here we synthesize recent evidence of DEL-1 as an exemplar local regulatory factor in the context of tissue immune plasticity and inflammatory disorders (such as periodontitis, multiple sclerosis, and pulmonary disorders), and discuss its potential as a therapeutic agent.

Keywords: DEL-1; EDIL3; homeostasis; inflammation; integrins; myelopoiesis; periodontitis; resolution.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Del-1 regulates the production and recruitment of neutrophils and apoptotic neutrophil clearance.

In the bone marrow, DEL-1 acts as a niche factor that promotes myelopoiesis. Specifically, DEL-1 interacts with β3 integrin on hematopoietic stem cells (HSCs) and induces HSC proliferation and biased differentiation toward the myeloid lineage (MyP, myeloid progenitors). In the vessel lumen, endothelial-cell derived DEL-1 blocks the interaction between LFA-1 (αLβ2) integrin on neutrophils and ICAM-1 on the vascular endothelium, thereby inhibiting neutrophil adhesion and transmigration. DEL-1 can also block Mac-1 (αMβ2) integrin, which mediates intraluminal crawling of neutrophils, although whether DEL-1 inhibits crawling has not been specifically addressed. Moreover, DEL-1 promotes macrophage efferocytosis and resolution of inflammation. Mechanistically, DEL-1 binds to the ‘eat-me’ signal phosphatidylserine (PS) on apoptotic cells as well as to the αvβ3 integrin on macrophages, thereby acting as an efferocytic ‘bridge’ that enhances apoptotic cell phagocytosis. ECM, extracellular matrix; ICAM, intercellular adhesion molecule; PS, phosphatidylserine.

Figure 2.. The DEL-1–IL-17 balance in immunity and inflammation.

In steady state, the reciprocal regulation between DEL-1 and IL-17 maintains a balance between the protective and detrimental effects of neutrophil recruitment thereby contributing to homeostatic immunity. However, in old age or in inflammatory disorders, the balance is tilted towards IL-17, which can directly downregulate DEL-1 expression, thereby potentiating neutrophil recruitment. Low levels or deficiency of DEL-1 is associated with enhanced IL-17 levels, thereby predisposing to IL-17-driven inflammatory disease (e.g., inflammatory bone loss).

Figure 3.. IL-17 downregulates endothelial DEL-1 expression.

IL-17 (e.g., derived from Th17 cells or γδ T cells) interacts with the IL-17 receptor complex (IL-17RA/IL-17RC) and inhibits DEL-1 expression through a glycogen synthase kinase 3β (GSK3β)-dependent mechanism, which inhibits the binding of the critical transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) to the promoter of the DEL-1-encoding gene (EDIL3). This inhibitory action of IL-17 is counteracted at the GSK3β level by the pro-resolving lipid mediator resolvin D1 (RvD1) in a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner. This activity of RvD1 (which may derive from resolving macrophages) is mediated through interactions with specific receptors, the G-protein-coupled receptor 32 (GPR32) and the lipoxin A4 receptor/formyl-peptide receptor-2 (ALX/FPR2).

Figure 4.. Location principle.

Endothelial cell-derived DEL-1 primarily regulates inflammation initiation by restraining LFA-1/ICAM-1-dependent neutrophil recruitment, whereas macrophage-derived DEL-1 promotes the resolution of inflammation. In this regard, DEL-1 enhances efferocytosis and LXR-dependent reprogramming of the efferocytic macrophage that can upregulate pro-resolving factors, such as TGFβ and resolvins. Resolvins may contribute to the rising levels of DEL-1 during resolution, for instance, by counteracting inhibitory mechanisms that would otherwise suppress DEL-1 expression. Together, these observations suggest the operation of a feed-forward loop that links DEL-1 and resolvins and reinforces inflammation resolution. These location-dependent homeostatic functions facilitate the spatiotemporal regulation of the immune response by the same multifunctional molecule, DEL-1. ICAM-1, intercellular adhesion molecule 1; LFA-1, lymphocyte function-associated antigen 1; LXR, liver X receptor; PS, phosphatidylserine.