Adaptive immune cells in calcific aortic valve disease

Raddatz, Michael A.; Madhur, Meena S; Merryman, W. David

doi:10.1152/ajpheart.00100.2019

Cited by 50 publications

(38 citation statements)

References 191 publications

(229 reference statements)

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“…The role of immune cells in CAVS is not fully understood. Infiltration of T and B cells takes place in advanced stages of aortic valve stenosis and has been associated with the promotion of pro-inflammatory processes [11]. Macrophages are the immune cell type that is mainly infiltrating aortic valves in large numbers [2,12].…”

Section: Introductionmentioning

confidence: 99%

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

Karadimou

Plunde

Pawelzik

et al. 2020

Cells

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Calcific aortic valve stenosis (CAVS) is a common age-related disease characterized by active calcification of the leaflets of the aortic valve. How innate immune cells are involved in disease pathogenesis is not clear. In this study we investigate the role of the pattern recognition receptor Toll-like receptor 7 (TLR7) in CAVS, especially in relation to macrophage subtype. Human aortic valves were used for mRNA expression analysis, immunofluorescence staining, or ex vivo tissue assays. Response to TLR7 agonist in primary macrophages and valvular interstitial cells (VICs) were investigated in vitro. In the aortic valve, TLR7 correlated with M2 macrophage markers on mRNA levels. Expression was higher in the calcified part compared with the intermediate and healthy parts. TLR7+ cells were co-stained with M2-type macrophage receptors CD163 and CD206. Ex vivo stimulation of valve tissue with the TLR7 ligand imiquimod significantly increased secretion of IL-10, TNF-α, and GM-CSF. Primary macrophages responded to imiquimod with increased secretion of IL-10 while isolated VICs did not respond. In summary, in human aortic valves TLR7 expression is associated with M2 macrophages markers. Ex vivo tissue challenge with TLR7 ligand led to secretion of immunomodulatory cytokine IL-10. These results connect TLR7 activation in CAVS to reduced inflammation and improved clearance.

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Section: Introductionmentioning

confidence: 99%

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

Karadimou

Plunde

Pawelzik

et al. 2020

Cells

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“…While the cardiovascular immunology field has developed at a rapid pace, the role of immune cells in CAVD has remained unclear. 9,44 Here, we have focused on macrophages, which make up the majority of hematopoietic cells in the AV in both health and disease. 8 We have shown that Notch1 +/-AVICs promote macrophage maturation and infiltration, and that macrophages promote AVIC calcification through STAT3-dependent mechanisms (Fig 6).…”

Section: Discussionmentioning

confidence: 99%

“…Immune cells, and specifically macrophages, are linked to CAVD, 7 and up to 10-15% of cells in the healthy valve are CD45 + , a hematopoietic lineage marker. 8,9 These cells are primarily major histocompatibility complex II + (MHCII + ) macrophages. 8,10 M1-like macrophages, of which MHCII positivity is a marker, are more metabolically active, direct a proinflammatory immune response, and are further increased in CAVD.…”

Section: Introductionmentioning

confidence: 99%

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

et al. 2020

Preprint

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ObjectiveMacrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in calcification using the Notch1 +/model of calcific aortic valve disease. Approach and ResultsMacrophages in wild-type and Notch1 +/murine aortic valves were characterized by flow cytometry. Macrophages in Notch1 +/aortic valves had increased expression of MHCII. We then used bone marrow transplants to test if differences in Notch1 +/macrophages drive disease.Notch1 +/mice had increased valve thickness, macrophage infiltration, and M1-like macrophage polarization regardless of transplanted bone marrow genotype. In vitro approaches confirm that Notch1 +/aortic valve cells promote macrophage invasion as quantified by migration index and M1-like polarization quantified by Ly6C and CCR2 positivity regardless of macrophage genotype. Finally, we found that macrophage interaction with aortic valve cells promotes osteogenic, but not dystrophic, calcification by decreasing abundance of the STAT3β isoform. ConclusionsThis study reveals that Notch1 +/aortic valve disease involves increased macrophage recruitment and polarization driven by altered aortic valve cell secretion, and that increased macrophage recruitment promotes osteogenic calcification through STAT3 splicing changes.Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in calcific aortic valve disease is warranted.

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“…It is possible that the myofibroblast activation phenotype may be a bimodal distribution and if a longer time course was studied, more mice would develop the elevated αSMA phenotype seen in one Notch1 +/-;Htr2b +/+ mouse. However, when combined with collagen deposition based on trichrome staining, it appears the myofibroblast-driven fibrotic phenotype is likely not the cause of the differing phenotype which may point to a difference in glycosaminoglycan structure, osteogenic calcification, or cellular inflammation (6,30,31). Notch1 is known to downregulate…”

Section: Discussionmentioning

confidence: 99%

Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics in a high-cholesterol diet mouse model

Joll

Clark

Peters

et al. 2020

Preprint

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Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT 2B serotonin receptor (gene: Htr2b ) could improve the hemodynamic and histological progression of calcific aortic valve disease. Htr2b mutant mice were crossed with Notch1 +/- mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression, Notch1 +/- mice were treated with the 5-HT 2B receptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction. Htr2b mutant mice showed lower aortic valve peak velocity and mean pressure gradient – classical hemodynamic indicators of aortic valve stenosis – without concurrent left ventricle change. 5-HT 2B receptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation of Htr2b attenuates hemodynamic development of CAVD in the Notch1 +/- mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.

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Adaptive immune cells in calcific aortic valve disease

Cited by 50 publications

References 191 publications

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics in a high-cholesterol diet mouse model

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