Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination

Choi, Eun Young; Lim, Jin Ho; Neuwirth, Aleš; Economopoulou, Matina; Chatzigeorgiou, Antonios; Chung, Kyoung‐Jin; Bittner, Stefan; Lee, Seung Hwan; Langer, Harald F.; Samus, Maryna; Kim, Hyesoon; Cho, Geum-Sil; Ziemssen, Tjalf; Bdeir, Khalil; Chavakis, Emmanouil; Koh, Jae‐Young; Boon, Louis; Hosur, Kavita B.; Bornstein, Stefan R.; Meuth, Sven G.; Hajishengallis, George; Chavakis, Triantafyllos

doi:10.1038/mp.2014.146

Cited by 72 publications

(124 citation statements)

References 52 publications

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“…Therefore, the homeostatic function of Del-1 is not restricted to regulation of inflammatory cell recruitment to peripheral tissues as we showed earlier (29,31,65), but also involves control of their progenitors in the BM. As febrile neutropenia, associated with chemotherapy or HSC transplantation, is a major cause for morbidity and mortality (25), the herein identified role of Del-1 in the induction and maintenance of proper de novo granulopoiesis is important and could be therapeutically exploited in this context.…”

Section: Cell Cycle Analysis Of Lt-hscs From Edil3mentioning

confidence: 53%

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Mitroulis¹,

Chen²,

Singh³

et al. 2017

Journal of Clinical Investigation

124

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es. We show that Del-1, via its interaction with the αvβ3 integrin, promotes several critical functions in the niche, including HSC retention, hematopoietic progenitor cell cycle progression, and myeloid lineage commitment of HSCs. Del-1 thereby regulates myelopoiesis under steady-state conditions and in G-CSF-or inflammation-induced stress myelopoiesis, as well as myelopoiesis reconstitution under regenerative/transplantation conditions. Del-1 is hence a niche component that serves a juxtacrine homeostatic adaptation of the hematopoietic system in inflammation-related and regeneration myelopoiesis. ResultsDel-1 expression in the BM. First, we sought to investigate whether Del-1 is present in the BM. We initially studied the expression of the Del-1-encoding gene Edil3 in the BM niche and hematopoietic cell populations. We found that Edil3 mRNA expression was significantly higher in the endosteal region as compared with the central BM (cBM) ( Figure 1A), suggesting that Del-1 is enriched at the endosteal area of the BM. Analysis of sorted cells from CXCL12-GFP mice (33, 34) demonstrated that Edil3 was highly expressed integrin receptors (29-31). It consists of three N-terminal EGF-like repeats and two C-terminal discoidin I-like domains, and hence also is designated EGF-like repeats and discoidin-I-like domains-3 (EDIL3) (32). We have previously identified Del-1 as an endogenous modulator of leukocyte adhesion through interaction with integrin αLβ2 (LFA-1; CD11a/CD18) (29, 31). Moreover, Del-1 interacts with β3 integrin (CD61) via an Arg-Gly-Asp (RGD) motif on the second EGF-like repeat (30).In the present work, we observed that Del-1 is expressed by several major cellular components of the HSC niche, though not by hematopoietic progenitors. In particular, Del-1 is expressed by those niche cells that have a major role in the maintenance of HSCs, i.e., arteriolar endothelial cells and perivascular CAR cells (3,6,7,9,15). In addition, Del-1 is expressed by cells of the osteoblastic lineage that crucially mediate the engraftment of HSCs in the post-transplantation niche (3,17,18). This spatial distribution of Del-1 raised the possibility that it might be involved in the regulation of hematopoiesis. We addressed this hypothesis using in vivo models of steady-state, regenerative, and stress hematopoiesis and in vitro mechanistic approach-

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Section: Cell Cycle Analysis Of Lt-hscs From Edil3mentioning

confidence: 53%

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Mitroulis¹,

Chen²,

Singh³

et al. 2017

Journal of Clinical Investigation

124

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“…Lastly, Del-1 was recently revealed to inhibit leukocyte recruitment in the inflammatory process by binding β 2 -integrin and thereby antagonizing integrindependent leukocyte adhesion to the endothelium [6,21,22]. For example, Del-1-deficient mice develop spontaneous inflammation characterized by excessive neutrophil infiltration [21] or autoimmune disease such as encephalomyelitis, a murine model of multiple sclerosis, suggesting that Del-1 may play a role in the immune tolerance of host immune cells against cancer cells [23]. Thus, when combining the effects of Del-1 on immune and cancer cells, the impact of Del-1 on survival may be compromised based on its anti-inflammatory effect and augmentation of cancer progression and epithelial-mesenchymal transition.…”

Section: Discussionmentioning

confidence: 99%

“…While this discrepancy can be partially explained by tissue or organ specificity in transcriptional regulation or tumor microenvironments and differences in disease status [23], further basic and clinical studies are warranted to clarify the exact role of Del-1 and its alteration in expression.…”

Section: Discussionmentioning

confidence: 99%

Del-1 Expression as a Potential Biomarker in Triple-Negative Early Breast Cancer

Lee

Kim

et al. 2018

Oncology

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Objective: A differential diagnostic role for plasma Del-1 was proposed for early breast cancer (EBC) in our previous study. We examined tumoral Del-1 expression and analyzed its prognostic impact among patients with EBC. Methods: Del-1 mRNA expression was assessed in breast epithelial and cancer cells. Meanwhile, the tumoral expression of Del-1 was determined based on tissue microarrays and immunohistochemistry results from 440 patients. Results: While a high Del-1 mRNA expression was found in all the breast cancer cell lines, the expression was significantly higher in MDA-MB-231. Tumoral expression of Del-1 was also significantly associated with a negative expression of estrogen receptor or progesterone receptor, and low expression of Ki-67, particularly in the case of triple-negative breast cancer (TNBC) (p < 0.036). Furthermore, a correlation was found between Del-1 expression and an aggressive histological grade, nuclear mitosis, and polymorphism, suggesting a possible role in tumor progression. In the survival analysis, a worse distant disease-free survival trend was noted for the group overexpressing Del-1. Conclusion: While all the investigated breast cancer cell lines exhibited Del-1 expression, the expression rate and intensity were specifically prominent in TNBC. In addition, based on its relationship to an unfavorable histology and worse survival trend, Del-1 could act as a molecular target in TNBC patients.

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“…Del-1-deficiency resulted in enhanced EAE disease severity, accompanied by elevated IL-17-dependent neuro-inflammation. Interestingly, administration of soluble Del-1 ameliorated progression of relapsing-remitting EAE (Choi et al, 2014 in press). Together, application of Del-1 may represent a promising therapeutic approach in IL-17-dependent inflammatory disorders.…”

Section: Endogenous Inhibitors Of Leukocyte Recruitmentmentioning

confidence: 99%

Leukocyte integrins: Role in leukocyte recruitment and as therapeutic targets in inflammatory disease

Mitroulis

Alexaki

Kourtzelis

et al. 2015

Pharmacology & Therapeutics

226

217

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Infection or sterile inflammation triggers site-specific attraction of leukocytes. Leukocyte recruitment is a process comprising several steps orchestrated by adhesion molecules, chemokines, cytokines and endogenous regulatory molecules. Distinct adhesive interactions between endothelial cells and leukocytes and signalling mechanisms contribute to the temporal and spatial fine-tuning of the leukocyte adhesion cascade. Central players in the leukocyte adhesion cascade include the leukocyte adhesion receptors of the β2-integrin family, such as the αLβ2 and αMβ2 integrins, or of the β1-integrin family, such as the α4β1- integrin. Given the central involvement of leukocyte recruitment in different inflammatory and autoimmune diseases, the leukocyte adhesion cascade in general, and leukocyte integrins in particular, represent key therapeutic targets. In this context, the present review focuses on the role of leukocyte integrins in the leukocyte adhesion cascade. Experimental evidence that has implicated leukocyte integrins as targets in animal models of inflammatory disorders, such as experimental autoimmune encephalomyelitis, psoriasis, inflammatory bone loss and inflammatory bowel disease as well as preclinical and clinical therapeutic applications of antibodies that target leukocyte integrins in various inflammatory disorders are presented. Finally, we review recent findings on endogenous inhibitors that modify leukocyte integrin function, which could emerge as promising therapeutic targets.

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Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination

Cited by 72 publications

References 52 publications

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Del-1 Expression as a Potential Biomarker in Triple-Negative Early Breast Cancer

Leukocyte integrins: Role in leukocyte recruitment and as therapeutic targets in inflammatory disease

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