| 1. |
- Strom, Asa C., et al.
(författare)
-
B regulatory cells are increased in hypercholesterolaemic mice and protect from lesion development via IL-10
- 2015
-
Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 114:4, s. 835-847
-
Tidskriftsartikel (refereegranskat)abstract
- Whilst innate B1-B cells are atheroprotective, adaptive B2-B cells are considered pro-atherogenic. Different subsets of B regulatory cells (B-reg) have been described. In experimental arthritis and lupus-like disease, B-reg are contained within the CD21(hi)CD23(hi)CD24(hi) B cell pool The existence and role of B-reg in vascular disease is not known. We sought to investigate the existence, identity and location of B-reg in vascular disease. The representation of B2-B cell subsets in the spleens and lymph nodes (LNs) of Apolipoprotein E-/- (ApoE(-/-)) mice compared to controls was characterised by flow cytometry. Additionally, we utilised a model of neointima formation based on the placement of a perivascular collar around the carotid artery in ApoE(-/-) mice to ascertain whether B cells and B cell subsets confer protection against lesion development. Adoptive transfer of B cells was performed from wild type or genetically modified mice. We showed that CD21(hi)CD23(hi)CD24(hi) B cells are unexpectedly increased in the draining LNs of ApoE(-/-) mice. Adoptive transfer of LN-derived B2-B cells or purified CD21(hi)CD23(hi)CD24(hi) B cells to syngeneic mice reduced lesion size and inflammation without changing serum cholesterol levels. Follicular B2-B cells did not confer protection. IL-10 blockade or transfer of IL10-deficient B cells prevented LN-derived B cell-mediated protection. This is the first identification of a specific LN-derived B2-B-reg subset that confers IL-10 mediated protection from neointima formation. This may open the way for immune modulatory approaches in cardiovascular disease.
|
|
| 2. |
- Seneviratne, Anusha N., et al.
(författare)
-
Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis
- 2017
-
Ingår i: Circulation. - 0009-7322. ; 136:5, s. 1140-1154
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND—: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis), promotes lesion growth and establishment of a necrotic core. The transcription factor Interferon Regulatory Factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions. METHODS—: We investigated the role of IRF5 in atherosclerosis in two complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE) mice and ApoE mice with a genetic deletion of IRF5 (ApoEIrf5) was compared then lesion development was assessed in a model of shear stress modulated vulnerable plaque formation. RESULTS—: Both lesion size and necrotic core size were significantly reduced in ApoEIrf5 mice compared to IRF5 competent ApoE mice. Necrotic core size was also reduced in the model of shear stress modulated vulnerable plaque formation. A significant loss of CD11c macrophages was evident in ApoEIrf5 mice in the aorta, draining lymph nodes and in bone marrow cell cultures, indicating that IRF5 maintains CD11c macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c macrophages displayed a significant increase in expression of the efferocytosis regulating integrin-β3 and its ligand milk fat globule-EGF factor 8 protein (Mfge8) and enhanced efferocytosis in vitro and in situ. CONCLUSIONS—: IRF5 is detrimental in atherosclerosis by promoting the maintenance of pro-inflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
|
|
