Therapeutic CCR2 Blockade Prevents Inflammation and Alleviates Myxomatous Valve Disease in Marfan Syndrome

Xu, Na; Yutzey, Katherine E.

doi:10.1016/j.jacbts.2022.06.001

Cited by 9 publications

(14 citation statements)

References 29 publications

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“…Our findings support the idea that inflammatory mechanisms contribute to pathological extracellular matrix remodeling and that the innate immune system plays a significant role in canine MMVD progression ( Table 2 , Section 3.2.6 ). These findings strengthen previously discovered similarities between not only canine and human MMVD but also between human MMVD and MMVD in pigs, mice, and sheep, species in which populations of multiple immune cells increase in number with MMVD [ 36 ]. Finally, we have addressed cell and tissue hemostasis ( Section 3.2.7 ) and anemia of chronic disease ( Section 3.2.8 ) as the biological pathways and mechanisms that showed up as important in canine MMVD pathology ( Table 2 and Figure 5 ).…”

Section: Discussionsupporting

confidence: 90%

“…According to our results ( Figure 2 ), the CCL14 activity is the highest early in disease onset (MMVD stage B1), increases again with the development of CHF (stage C), and is higher in the B1 stage than in the B2 stage. Interestingly, mitral valve inflammation and inflammatory proteases were reduced in the C-C chemokine receptor type 2 genetic knockout mouse model, while C-C chemokine receptor type 2 antagonist RS504393 therapy, early on or in a late phase, ameliorates myxomatous valve degeneration and valve leaflet thickness in Fbn1C1039G/+ mice [ 36 ]. A similar experimental approach may be implemented for investigating C-C motif chemokine receptor type 14 + immune cells.…”

Section: Discussionmentioning

confidence: 99%

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Serum Proteomic Profiles Reflect the Stages of Myxomatous Mitral Valve Disease in Dogs

Maslov

Farkaš

Rubić

et al. 2023

IJMS

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Canine myxomatous mitral valve disease (MMVD) is similar to Barlow’s form of MMVD in humans. These valvulopathies are complex, with varying speeds of progression. We hypothesized that the relative abundances of serum proteins would help identify the consecutive MMVD stages and discover new disease pathways on a systemic level. To identify distinction-contributing protein panels for disease onset and progression, we compared the proteomic profiles of serum from healthy dogs and dogs with different stages of naturally occurring MMVD. Dogs were divided into experimental groups on the basis of the left-atrium-to-aorta ratio and normalized left ventricular internal dimension in diastole values. Serum was collected from healthy (N = 12) dogs, dogs diagnosed with MMVD in stages B1 (N = 13) and B2 (N = 12) (asymptomatic), and dogs diagnosed with MMVD in chronic stage C (N = 13) (symptomatic). Serum biochemistry and selected ELISAs (galectin-3, suppression of tumorigenicity, and asymmetric dimethylarginine) were performed. Liquid chromatography–mass spectrometry (LC–MS), tandem mass tag (TMT) quantitative proteomics, and statistical and bioinformatics analysis were employed. Most of the 21 serum proteins with significantly different abundances between experimental groups (p < 0.05, FDR ˂ 0.05) were classified as matrix metalloproteinases, protease inhibitors, scaffold/adaptor proteins, complement components, anticoagulants, cytokine, and chaperone. LC–MS TMT proteomics results obtained for haptoglobin, clusterin, and peptidase D were further validated analytically. Canine MMVD stages, including, for the first time, asymptomatic B1 and B2 stages, were successfully distinguished in dogs with the disease and healthy dogs on the basis of the relative abundances of a panel of specific serum proteins. Most proteins with significantly different abundances were involved in immune and inflammatory pathways. Their role in structural remodeling and progression of canine MMVD must be further investigated. Further research is needed to confirm the resemblance/difference with human MMVD. Proteomics data are available via ProteomeXchange with the unique dataset identifier PXD038475.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Serum Proteomic Profiles Reflect the Stages of Myxomatous Mitral Valve Disease in Dogs

Maslov

Farkaš

Rubić

et al. 2023

IJMS

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“… 2 Therefore, echocardiographic analysis alone may not be sufficient to identify those at-risk patients early, before the development of valvular prolapse and debilitating secondary complications. However here, Xu and Yutzey 4 also reported the clinical potential of implementing RS504393 as a treatment strategy for myxomatous valve degeneration by injecting 6-month-old Fbn1 C1039/+ mice for 30 days, which successfully restored myxomatous changes including leaflet thickness and excess proteoglycan accumulation.…”

mentioning

confidence: 75%

“…In this issue of JACC : Basic to Translational Science , Xu and Yutzey 4 dig deeper into the role of immune cells in mitral valve disease by mechanistically demonstrating that immune processes are the main pathogenic drivers of mitral valve disease in the Fbn1 C1039/fl mouse model of Marfan syndrome. The authors applied bulk RNA-seq and showed that the phenotypic “rescue” of mitral valve disease in the previously reported CCR2-deficient Fbn1 C1039/+ mice 3 is caused by restored low levels of inflammatory-enriched mRNAs, including associated inflammatory proteases (chymases, carboxypeptidases).…”

mentioning

confidence: 99%

Immune Cells, Superheroes or Villains?

Lincoln

2022

JACC: Basic to Translational Science

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“…There are several genetically modified mice that have been used to investigate monocyte migration and trafficking, including the knock-in/knock-out Cx3cr1 GFP and later the Ccr2 RFP reporter strain, in which the respective genes are replaced by fluorescence reporter genes [15,20,39]. These mice have been used in many studies and differential surface expression of CX3CR1 has been assumed based on the differences in GFP expression [15,[49][50][51]. However, using five different anti-CX3CR1 antibodies and two different reporter mouse models, we show that this is actually not the case, and the CX3CR1 reporter signals do not match the actual surface expression of CX3CR1, as detected by anti-CX3CR1 antibodies.…”

Section: Discussionmentioning

confidence: 99%

Discrepant Phenotyping of Monocytes Based on CX3CR1 and CCR2 Using Fluorescent Reporters and Antibodies

Sommer,

Garibagaoglu,

Paap

et al. 2024

Cells

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Monocytes, as well as downstream macrophages and dendritic cells, are essential players in the immune system, fulfilling key roles in homeostasis as well as in inflammatory conditions. Conventionally, driven by studies on reporter models, mouse monocytes are categorized into a classical and a non-classical subset based on their inversely correlated surface expression of Ly6C/CCR2 and CX3CR1. Here, we aimed to challenge this concept by antibody staining and reporter mouse models. Therefore, we took advantage of Cx3cr1GFP and Ccr2RFP reporter mice, in which the respective gene was replaced by a fluorescent reporter protein gene. We analyzed the expression of CX3CR1 and CCR2 by flow cytometry using several validated fluorochrome-coupled antibodies and compared them with the reporter gene signal in these reporter mouse strains. Although we were able to validate the specificity of the fluorochrome-coupled flow cytometry antibodies, mouse Ly6Chigh classical and Ly6Clow non-classical monocytes showed no differences in CX3CR1 expression levels in the peripheral blood and spleen when stained with these antibodies. On the contrary, in Cx3cr1GFP reporter mice, we were able to reproduce the inverse correlation of the CX3CR1 reporter gene signal and Ly6C surface expression. Furthermore, differential CCR2 surface expression correlating with the expression of Ly6C was observed by antibody staining, but not in Ccr2RFP reporter mice. In conclusion, our data suggest that phenotyping strategies for mouse monocyte subsets should be carefully selected. In accordance with the literature, the suitability of CX3CR1 antibody staining is limited, whereas for CCR2, caution should be applied when using reporter mice.

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Therapeutic CCR2 Blockade Prevents Inflammation and Alleviates Myxomatous Valve Disease in Marfan Syndrome

Cited by 9 publications

References 29 publications

Serum Proteomic Profiles Reflect the Stages of Myxomatous Mitral Valve Disease in Dogs

Serum Proteomic Profiles Reflect the Stages of Myxomatous Mitral Valve Disease in Dogs

Immune Cells, Superheroes or Villains?

Discrepant Phenotyping of Monocytes Based on CX3CR1 and CCR2 Using Fluorescent Reporters and Antibodies

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