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

Abstract

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.

Omega-3 Polyunsaturated Fatty Acids and the Resolution of Inflammation: Novel Therapeutic Opportunities for Aortic Valve Stenosis?

“…In support of RvE1 signaling affecting the valvular macrophage subtype, the mRNA levels of its receptor ChemR23 are significantly correlated with the expression of markers of M2-type macrophages in human stenotic valves ( Artiach et al, 2020a ). Similar associations have been reported also for Toll-like receptor (TLR) 7 in stenotic aortic valves and stimulation of macrophages with a TLR7 agonist induced release of the anti-inflammatory cytokine IL-10 ( Karadimou et al, 2020 ), hence reinforcing the role of M2 macrophages in the resolution of valvular inflammation. Moreover, exogenous administration of RvE1 to cultured VIC reduced in vitro calcification, suggesting that omega-3 PUFA-derived SPMs in addition to altering the valvular immune response also directly act on the structural cells of the valve to counteract calcification.…”

“…Stimulating SPMs and their receptors have beneficial effects in several animal models of intimal hyperplasia ( Artiach et al, 2018 ; Liu et al, 2018 ), atherosclerosis ( Petri et al, 2017 ), and vascular calcification ( Carracedo et al, 2018 ). Recently, studies on SPM pathways ( Artiach et al, 2020a ) and M2 macrophages ( Karadimou et al, 2020 ) pointed toward a failure in the resolution of inflammation as part of the pathophysiological processes underlying the chronic inflammation in AVS.…”

In situ injectable hydrogel-loaded drugs induce anti-tumor immune responses in melanoma immunochemotherapy

“…8 A and 8I-K), which indicated that M1 macrophages were activated and the infiltration of M2 macrophages decreased in the tumor sites after the Dox/hydrogel treatment. We also found that the rate of CD206+ cells in the co-delivering treated group showed no significant difference compared with that of the control group, which might due to the stimulation of R837 on M2 macrophages [ 54 ]. In a word, the analysis of infiltrated immune cells revealed that multiple types of immune promoted cells have been activated and infiltrated in the tumor sites after the co-delivering treatment, while the infiltration of immune suppressive M2 macrophages decreased.…”

Calcified aortic valve disease complicated with and without diabetes mellitus: the underlying pathogenesis

“…Toll-like receptors are expressed by VICs. They promote osteogenic phenotype of VICs [51,52]. NFκB is activated by TNFα from T-lymphocytes and macrophages [53].…”