Notch signaling mediates crosstalk between endothelial cells and macrophages via Dll4 and IL6 in cardiac microvascular inflammation

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• 作者：Angé ; lique Pabois^a ; ^b ; ^c ; ¹ ; Sylvain Pagie^a ; ^b ; ^c ; ¹ ; Nathalie Gé ; rard^a ; ^b ; Christian Laboisse^d ; Sabine Pattier^e ; Philippe Hulin^c ; ^f ; Steven Nedellec^c ; ^f ; Claire Toquet^d ; Bé ; atrice Charreau^a ; ^b ; ^c ; ^{Beatrice.Charreau@univ-nantes.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ADAM ; a disintegrin and a metalloproteinase ; AMR ; antibody-mediated rejection ; Arg1 ; Arginase 1 ; CAV ; cardiac allograft vasculopathy ; CBF1 ; C promoter Binding Factor 1 ; DAPT ; N-[N-(3 ; 5-Difluorophenacetyl)-l-alanyl]-Sphenylglycine t-butyl ester ; Dll ; Delta-like ; DSA ; donor specific alloantibodies ; EMB ; endomyocardial biopsies ; Hes ; hairy enhancer of split ; Hey ; hairy related ; IRF5 ; Interferon regulatory factor 5 ; NFH ; non failing heart ; NICD ; Notch intracellular domain
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：104
• 期：Complete
• 页码：95-107
• 全文大小：2160 K

文摘

Although short-term outcomes have improved with modern era immunosuppression, little progress has been made in long-term graft survival in cardiac transplantation. Antibody-mediated rejection (AMR) is one of the leading causes of graft failure and contributes significantly to poor long-term outcomes. Endothelial cell (EC) injury, intravascular macrophage infiltrate and microvascular inflammation are the histological features of AMR. Nevertheless, mechanisms of AMR remain unclear and treatment is still limited. Here, we investigated the mechanisms underlying vascular and inflammatory cell network involved in AMR at endothelial and macrophage levels, using endomyocardial transplant biopsies and EC/monocyte cocultures. First, we found that AMR associates with changes in Notch signaling at endothelium/monocyte interface including loss of endothelial Notch4 and the acquisition of the Notch ligand Dll4 in both cell types. We showed that endothelial Dll4 induces macrophage polarization into a pro-inflammatory fate (CD40^highCD64^highCD200R^low HLA-DR^lowCD11b^low) eliciting the production of IL-6. Dll4 and IL-6 are both Notch-dependent and are required for macrophage polarization through selective down and upregulation of M2- and M1-type markers, respectively. Overall, these findings highlight the impact of the graft’s endothelium on macrophage recruitment and differentiation upon AMR via Notch signaling. We identified Dll4 and IL-6 as coregulators of vascular inflammation in cardiac transplantation and as potential targets for immunotherapy.