DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates

Shin, Jieun; Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia; Hosur, Kavita B.; Pyaram, Kalyani; Mitroulis, Ioannis; Chavakis, Triantafyllos; Hajishengallis, George

doi:10.1126/scitranslmed.aac5380

Cited by 94 publications

(141 citation statements)

References 43 publications

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“…Since Del-1 blocks LFA-1 binding to its ligand ICAM-1 and prevents neutrophil transmigration [50], it could be administered to inlamed tissues, to reduce neutrophil recruitment, and to reduce inlammation. In fact, this is exactly what was found in a model of periodontitis with nonhuman primates [75]. Local administration of Del-1 also prevented inlammatory bone loss [75].…”

Section: Therapeutic Approachessupporting

confidence: 67%

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Neutrophil Role in Periodontal Disease

Rosales¹,

Uribe‐Querol²

2017

Role of Neutrophils in Disease Pathogenesis

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Oral tissues are constantly exposed to damage from the mechanical efort of eating and from the invasion of foreign microorganisms such as bacteria, fungi, and virus. In healthy oral tissues, there is a balance between symbiotic bacteria and cells from the innate immune system, mainly neutrophils. When this balance is broken, inlammation appears and more immune cells are recruited to the gingiva. Neutrophils form a barrier against dysbiotic bacteria. However, when neutrophils are insuicient, bacteria thrive causing periodontitis, a chronic inlammatory disease that destroys the tooth-supporting tissues or periodontium. Damage of periodontal tissues leads to tooth loss, and in severe cases, it can also afect systemic health by increasing a person's risk for atherosclerosis, rheumatoid arthritis, diabetes, and even cancer. The mechanisms neutrophil employ to keep a balance with bacteria in order to maintain healthy oral tissues is the focus of this chapter. We discuss how neutrophil antimicrobial functions keep bacteria at check and how some dysbiotic bacteria block neutrophils to promote an inlammatory state. Also, novel therapeutic approaches for periodontitis are discussed.

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Section: Therapeutic Approachessupporting

confidence: 67%

“…In fact, this is exactly what was found in a model of periodontitis with nonhuman primates [75]. Local administration of Del-1 also prevented inlammatory bone loss [75]. Preclinical studies for the use of Del-1 are now underway.…”

Section: Therapeutic Approachessupporting

confidence: 52%

Neutrophil Role in Periodontal Disease

Rosales¹,

Uribe‐Querol²

2017

Role of Neutrophils in Disease Pathogenesis

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“…Because B and plasma cells are a major source of RANKL in the bone-resorptive lesions of chronic periodontitis [86], the abundance of B-lineage cells in LAD-I periodontitis might further contribute to inflammatory bone loss, secondarily to the dysregulated IL-17 response. Other secondary causes for bone loss in LAD-I periodontitis might be the deficiency of CD18 in osteoclasts, since Mac-1 (CD11b/CD18) is a negative regulator of osteoclastogenesis [87,88]. However, it should be noted that periodontal bone loss is arrested once teeth are removed or lost in LAD-I patients, who moreover have not been reported to have skeletal bone deficit.…”

Section: Concepts Derived From the Study Of Rare Monogenic Diseasesmentioning

confidence: 99%

Immune and regulatory functions of neutrophils in inflammatory bone loss

Hajishengallis

Moutsopoulos

Hajishengallis

et al. 2016

Seminars in Immunology

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113

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Although historically viewed as merely anti-microbial effectors in acute infection or injury, neutrophils are now appreciated to be functionally versatile with critical roles also in chronic inflammation. Periodontitis, a chronic inflammatory disease that destroys the tooth-supporting gums and bone, is particularly affected by alterations in neutrophil numbers or function, as revealed by observations in monogenic disorders and relevant mouse models. Besides being a significant debilitating disease and health burden in its own right, periodontitis is thus an attractive model to dissect uncharted neutrophil-associated (patho)physiological pathways. Here, we summarize recent evidence that neutrophils can contribute to inflammatory bone loss not only through the typical bystander injury dogma but intriguingly also through their absence from the affected tissue, where they normally perform important immunomodulatory functions. Moreover, we discuss recent advances in the interactions of neutrophils with the vascular endothelium and – upon extravasation – with bacteria, and how the dysregulation of these interactions leads to inflammatory tissue damage. Overall, neutrophils have both protective and destructive roles in periodontitis, as they are involved in both the maintenance of periodontal tissue homeostasis and the induction of inflammatory bone loss. This highlights the importance of developing approaches that promote or sustain a fine balance between homeostatic immunity and inflammatory pathology.

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“…Del-1−Fc generation has been previously described (30). An RGE point mutant of Del-1−Fc, in which Glu (E) was substituted for Asp (D) in the RGD motif of the second EGF repeat (Del-1[RGE]-Fc), was constructed by site-directed mutagenesis (QuickChange II mutagenesis kit; Agilent).…”

Section: Cell Cycle Analysis Of Lt-hscs From Edil3mentioning

confidence: 99%

“…An RGE point mutant of Del-1−Fc, in which Glu (E) was substituted for Asp (D) in the RGD motif of the second EGF repeat (Del-1[RGE]-Fc), was constructed by site-directed mutagenesis (QuickChange II mutagenesis kit; Agilent). Expression and purification were performed as described (30).…”

Section: Cell Cycle Analysis Of Lt-hscs From Edil3mentioning

confidence: 99%

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

Mitroulis¹,

Chen²,

Singh³

et al. 2017

Journal of Clinical Investigation

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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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DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates

Cited by 94 publications

References 43 publications

Neutrophil Role in Periodontal Disease

Neutrophil Role in Periodontal Disease

Immune and regulatory functions of neutrophils in inflammatory bone loss

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

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