The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution

Li, Xiaofei; Colamatteo, Alessandra; Kalafati, Lydia; Kajikawa, Tetsuhiro; Wang, Hui; Lim, Jin Ho; Bdeir, Khalil; Chung, Kyoung‐Jin; Yu, Xiang; Fusco, Clorinda; Porcellini, Antonio; Simone, Salvatore De; Matarese, Giuseppe; Chavakis, Triantafyllos; Rosa, Veronica De; Hajishengallis, George

doi:10.1172/jci137530

Cited by 34 publications

(28 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Specifically, factors regulating peripheral inflammation may in fact do so by additionally modulating central inflammatory processes. For instance, the homeostatic protein developmental endothelial locus 1 (DEL1; also known as EGF-like repeat and discoidin I-like domain-containing protein 3), which was shown to inhibit initiation of periodontal inflammation and to promote its resolution [144][145][146][147] , may also regulate central inflammatory processes via its function to modulate demand-adapted myelopoiesis in the bone marrow 148 .…”

Section: Wwwnaturecom/nrimentioning

confidence: 99%

Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities

2021

Self Cite

View full text Add to dashboard Cite

Periodontitis, a major inflammatory disease of the oral mucosa, is epidemiologically associated with other chronic inflammation-driven disorders, including cardio-metabolic, neurodegenerative and autoimmune diseases and cancer. Emerging evidence from interventional studies indicates that local treatment of periodontitis ameliorates surrogate markers of comorbid conditions. The potential causal link between periodontitis and its comorbidities is further strengthened by recent experimental animal studies establishing biologically plausible and clinically consistent mechanisms whereby periodontitis could initiate or aggravate a comorbid condition. This multi-faceted 'mechanistic causality' aspect of the link between periodontitis and comorbidities is the focus of this Review. Understanding how certain extra-oral pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation, including adaptation of bone marrow haematopoietic progenitors, may provide new therapeutic options to reduce the risk of periodontitis-associated comorbidities.

show abstract

Section: Wwwnaturecom/nrimentioning

confidence: 99%

Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities

2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…These interactions bridge apoptotic cells to macrophages and promote apoptotic cell phagocytosis (efferocytosis) and inflammation resolution (21). Consistent with these homeostatic functions, DEL-1 protects against inflammatory disorders in preclinical mouse or non-human primate models, including inflammatory bone loss in periodontitis, experimental autoimmune encephalomyelitis, pulmonary inflammation and fibrosis, and allergic asthma (16,18,20,(24)(25)(26).…”

Section: Introductionmentioning

confidence: 82%

“…As alluded to above, the anti-leukocyte recruitment function of DEL-1 depends on its interaction with the LFA-1 integrin (15,16). By interacting with avb3 integrin on different cell targets, DEL-1 regulates myelopoiesis (51), efferocytosis (21,23), osteogenic differentiation of progenitors (22), and regulatory T cell stability and function (24); and by binding αvβ6 integrin, DEL-1 regulates integrin-mediated activation of TGF-β (52). In this study, we showed that the interaction of DEL- Our findings are consistent with earlier reports that LFA-1 is required for optimal APCdependent T cell activation and induction of Ab responses in mice and humans (54,55).…”

Section: Discussionmentioning

confidence: 99%

Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis

Wang¹,

Li²,

Kajikawa³

et al. 2021

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

The secreted protein DEL-1 regulates inflammatory cell recruitment and protects against inflammatory pathologies in animal models. Here, we investigated DEL-1 in inflammatory arthritis using collagen-induced arthritis (CIA) and collagen Ab-induced arthritis (CAIA). In both models, mice with endothelial-specific overexpression of DEL-1 were protected from arthritis relative to WT controls, while arthritis was exacerbated in DEL-1-deficient mice. Compared to WT controls, mice with collagen VI promoter-driven overexpression of DEL-1 in mesenchymal cells were protected against CIA but not CAIA, suggesting a role for DEL-1 in the induction of the arthritogenic Ab response. Indeed, DEL-1 was expressed in perivascular stromal cells of the lymph nodes and inhibited T follicular helper (Tfh) and germinal center B cell responses. Mechanistically, DEL-1 inhibited dendritic cell-dependent induction of Tfh cells by targeting the LFA-1 integrin on T cells. Overall, DEL-1 restrained arthritis through a dual mechanism, one acting locally in the joints and associated with the anti-recruitment function of endothelial cell-derived DEL-1; the other mechanism acting systemically in the lymph nodes and associated with the ability of stromal cell-derived DEL-1 to restrain Tfh responses. DEL-1 may thus be a promising novel therapeutic for the treatment of inflammatory arthritis.

show abstract

“…Its efficacy has been tested in IL-17mediated inflammatory bone loss in mice and primates, as well as in a mouse model of multiple sclerosis (28,33,34). Besides leukocyte recruitment, DEL-1 exerts its immunomodulatory actions via resolution of inflammation by efferocytosis and induction of anti-inflammatory Treg response (35,36). The anti-recruitment action of DEL-1 is mediated via inhibition of β2-integrin/ICAM interaction, whereas efferocytosis and induction of Treg response are mediated via interaction of DEL-1 to αvβ3-integrin by its RGD sequence in the second EGF-repeat (29,37).…”

Section: Introductionmentioning

confidence: 99%

Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation

Failer¹,

Amponsah-Offeh²,

Neuwirth³

et al. 2022

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

The causative role of inflammation in hypertension-related cardiovascular diseases is evident and calls for development of specific immunomodulatory therapies. We tested the therapeutic efficacy and mechanisms of action of developmental endothelial locus-1 (DEL-1), an endogenous antiinflammatory factor, in angiotensin II (ANGII)-and DOCA (deoxycorticosterone acetate)-saltinduced cardiovascular organ damage and hypertension. By using mice with endothelial overexpression of DEL-1 (EC-Del1) and performing preventive and interventional studies by injecting recombinant DEL-1 in mice, we showed that DEL-1 improved endothelial function and abrogated aortic adventitial fibrosis, medial thickening and loss of elastin. DEL-1 also protected the mice from cardiac concentric hypertrophy, interstitial and perivascular coronary fibrosis and improved left-ventricular function and myocardial coronary perfusion. DEL-1 prevented aortic stiffness and abolished the progression of hypertension. Mechanistically, DEL-1 acted by inhibiting αvβ3-integrin dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized αvβ3-integrin dependent CD25+FoxP3+ Treg numbers and IL-10 levels, which were associated with decreased pro-inflammatory cell recruitment of inflammatory cells and reduced production of pro-inflammatory cytokines in cardiovascular organs. The demonstrated effects and immune-modulating mechanisms of DEL-1 in abrogation of cardiovascular remodeling and progression of hypertension identify DEL-1 as a potential therapeutic factor.

show abstract

The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution

Cited by 34 publications

References 87 publications

Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities

Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities

Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis

Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation

Contact Info

Product

Resources

About