Monocytes augment inflammatory responses in human aortic valve interstitial cells via β2-integrin/ICAM-1-mediated signaling

Luo, Zichao; The, Erlinda; Zhang, Peijian; Zhai, Yufeng; Yao, Qingzhou; Ao, Lihua; Zeng, Qingchun; Fullerton, David A.; Meng, Xianzhong

doi:10.1007/s00011-022-01566-2

Cited by 8 publications

(9 citation statements)

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“…Studies have reported that soluble ECM proteins, including biglycan and matrilin-2, are capable of elevating the osteogenic activity in human AVICs ( 14 , 30 ). Our recent studies found that soluble matrilin-2 enhances the interaction of monocytes with AVICs ( 20 ) and that activated monocytes secrete tumor necrosis factor (TNF)-α and Regulated upon activation, normal T cell expressed and secreted (RANTES) to up-regulate the osteogenic activity in human AVICs ( 31 ). IL-38 is a newly discovered anti-inflammatory cytokine ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…This finding is in line with the observation that blood IL-38 levels are lower in overweight subjects at greater risk for cardiovascular diseases ( 23 ). ICAM-1, VCAM-1, CCL2 (C-C motif chemokine ligand 2), and IL-6 are inflammatory mediators essential for leukocyte infiltration ( 20 , 34 ). ALP is a biomarker of early osteoblastic transition in AVICs and RUNX2 is an osteoblast biomarker ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…Soluble matrilin-2 has been found to elevate AVIC inflammosteogenic (inflammatory and osteogenic) activities via activation of Toll-like receptor 2 and Toll-like receptor 4 ( 14 , 17 , 19 ). Soluble matrilin-2 can also promote the interaction of monocytes with AVICs, leading to the enhancement of inflammatory activity in AVICs ( 20 ). Thus, soluble matrilin-2 plays a mechanistic role in the valvular inflammosteogenic activities that promotes CAVD progression.…”

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confidence: 99%

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Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

The

Graaf

Zhai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Calcific aortic valve disease (CAVD) is common in people over the age of 65. Progressive valvular calcification is a characteristic of CAVD and due to chronic inflammation in aortic valve interstitial cells (AVICs) resulting in CAVD progression. IL-38 is a naturally occurring anti-inflammatory cytokine; here, we report lower levels of endogenous IL-38 in AVICs isolated from patients’ CAVD valves compared to AVICs from non-CAVD valves. Recombinant IL-38 suppressed spontaneous inflammatory activity and calcium deposition in cultured AVICs. In mice, knockdown of IL-38 enhanced the production of inflammatory mediators in murine AVICs exposed to the proinflammatory stimulant matrilin-2. We also observed that in cultured AVICs matrilin-2 stimulation activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome with procaspase-1 cleavage into active caspase-1. The addition of IL-38 to matrilin-2–treated AVICs suppressed caspase-1 activation and reduced the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, runt-related transcription factor 2, and alkaline phosphatase. Aged IL-38–deficient mice fed a high-fat diet exhibited aortic valve lesions compared to aged wild-type mice fed the same diet. The interleukin-1 receptor 9 (IL-1R9) is the putative receptor mediating the anti-inflammatory properties of IL-38; we observed that IL-1R9–deficient mice exhibited spontaneous aortic valve thickening and greater calcium deposition in AVICs compared to wild-type mice. These data demonstrate that IL-38 suppresses spontaneous and stimulated osteogenic activity in aortic valve via inhibition of the NLRP3 inflammasome and caspase-1. The findings of this study suggest that IL-38 has therapeutic potential for prevention of CAVD progression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

The

Graaf

Zhai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…New insights have suggested that inflammation precedes valve calcification and increases the levels of cell adhesion molecules such as ICAM1 and VCAM1 [ 41 ], which are responsible for recruiting inflammatory cells such as monocytes and macrophages into the valvular tissue, and this increased expression ultimately results in the production of proinflammatory mediators that regulate osteogenic differentiation and calcification in aortic VICs [ 42 ]. Similarly, our latest study showed that the inflammatory response of VICs was enhanced by monocytes through by monocytes through binding the secreted factor integrin to ICAM1 [ 43 ]. Therefore, the inhibition of inflammation is an important measure to suppress the osteogenic response of aortic VICs.…”

Section: Discussionmentioning

confidence: 99%

Hesperetin, a Promising Dietary Supplement for Preventing the Development of Calcific Aortic Valve Disease

et al. 2022

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Background: No effective therapeutic agents for calcific aortic valve disease (CAVD) are available currently. Dietary therapy has been proposed as a novel treatment strategy for various diseases. As a flavanone, hesperetin is widely abundant in citrus fruits and has been proven to play a protective role against multiple diseases. However, the role of hesperetin in CAVD remains unclear. Methods: Human aortic valve interstitial cells (VICs) were isolated from aortic valve leaflets. A mouse model of aortic valve stenosis was constructed through direct wire injury (DWI). Immunoblotting, immunofluorescence staining, and flow cytometry were used to investigate the roles of sirtuin 7 (Sirt7) and nuclear factor erythroid 2-related factor 2 (Nrf2) in hesperetin-mediated protective effects in VICs. Results: Hesperetin supplementation protected the mice from wire-injury-induced aortic valve stenosis; in vitro, hesperetin suppressed the lipopolysaccharide (LPS)-induced activation of NF-κB inflammatory cytokine secretion and osteogenic factors expression, reduced ROS production and apoptosis, and abrogated LPS-mediated injury to the mitochondrial membrane potential and the decline in the antioxidant levels in VICs. These benefits of hesperetin may have been obtained by activating Nrf2–ARE signaling, which corrected the dysfunctional mitochondria. Furthermore, we found that hesperetin could directly bind to Sirt7 and that the silencing of Sirt7 decreased the effects of hesperetin in VICs and potently abolished the ability of hesperetin to increase Nrf2 transcriptional activation. Conclusions: Our work demonstrates that hesperetin plays protective roles in the aortic valve through the Sirt7–Nrf2–ARE axis; thus, hesperetin might be a potential dietary supplement that could prevent the development of CAVD.

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“…17 MATN2 is an extracellular matrix (ECM) protein which promotes inflammation by activating toll-like receptors and enhancing monocyte infiltration into tissues. 18,19 Although the effect was smaller, CSF3 (G-CSF, which promotes inflammation by stimulating neutrophil production), was associated with GI symptoms (OR=1.05), fatigue (OR=1.12) and anxiety/depression (OR=1.05) (fig 1C -E). 20 IL-6 was also associated with increased odds of cardiorespiratory symptoms (OR=1.06) and fatigue (OR=1.09) (fig 1B&C).…”

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confidence: 99%

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease

Liew,

Efstathiou,

Fontanella

et al. 2023

Preprint

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One in ten SARS-CoV-2 infections result in prolonged symptoms termed "long COVID", yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

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Monocytes augment inflammatory responses in human aortic valve interstitial cells via β2-integrin/ICAM-1-mediated signaling

Cited by 8 publications

References 51 publications

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

Hesperetin, a Promising Dietary Supplement for Preventing the Development of Calcific Aortic Valve Disease

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease

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