Mesenchymal Stromal Cells Modulate Monocytes Trafficking in Coxsackievirus B3-Induced Myocarditis

Miteva, Kapka; Pappritz, Kathleen; El-Shafeey, Muhammad; Dong, Fengquan; Ringe, Jochen; Tschöpe, Carsten; Linthout, Sophie Van

doi:10.1002/sctm.16-0353

Cited by 62 publications

(57 citation statements)

References 55 publications

(92 reference statements)

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“…reported findings (22), we demonstrate an enrichment of proinflammatory Ly6C high CCR2 high Cx3Cr1 low and Ly6C mid CCR2 high Cx3Cr1 low monocytes in the myocardium 7 d postinfection. Application of T regs was able to reduce LV Ly6C and CCR2 gene expression, as well as the number of cardiac proinflammatory monocytes/macrophages, which led us assume that T reg application has an impact on cardiac monocyte/macrophage infiltration.…”

Section: Discussionsupporting

confidence: 74%

“…Concomitantly, a decline of splenic anti-inflammatory Ly6C low CCR2 low Cx3Cr1 high monocytes was found in CVB3 + T reg mice vs. CVB3 mice, indicating a migration of those cells toward the heart. The abovementioned findings support the existence of a cardiosplenic axis (i.e., the mobilization of monocytes from the spleen toward the heart) (25) in the setting of CVB3-induced myocarditis (6,22) and imply how intravenous T reg application can modulate this axis. Infiltration of monocytes into the heart is a dynamic process that depends on cardiac chemokine expression, chemokine receptor expression on monocytes (33), and the spleen as monocyte reservoir.…”

Section: Discussionsupporting

confidence: 60%

“…In the spleen, extramedullary myelopoeisis takes place for monocyte production to further ensure the supply of monocytes during acute inflammation (35). We previously demonstrated that extramedullary myelopoiesis is increased during CVB3induced myocarditis (22). In line with results from Lee et al (26), who demonstrated that T reg cells restrain splenic extramedullary myelopoiesis via suppression of hemopoietic cytokine-producing T cells, we observed decreased levels of CD4 + GM-CSF + and CD4 + IL-3 + cells after T reg application, which indicates a T reg -mediated reduction in splenic myelopoeisis.…”

Section: Discussionmentioning

confidence: 99%

“…Splenocytes were isolated according to Van Linthout et al (21). For cardiac mononuclear cell isolation, we used the neonatal heart dissociation kit (Miltenyi Biotec) (22). Cells were then stained for CD11b, CD115, Ly6C, CCR2, and Cx3Cr1 (all Abs were purchased from BioLegend, San Diego, CA, USA) to determine the pro-and anti-inflammatory monocyte subsets.…”

Section: Splenocyte and Cardiac Mononuclear Cell Isolation And Flow Cmentioning

confidence: 99%

“…Cells were then stained for CD11b, CD115, Ly6C, CCR2, and Cx3Cr1 (all Abs were purchased from BioLegend, San Diego, CA, USA) to determine the pro-and anti-inflammatory monocyte subsets. In addition, splenocytes were stained for CD4, CD8a, IL-10, IFN-g, IL-3 (all Miltenyi Biotec), IL-17, and GM-CSF (both BioLegend) according to previously established protocols (6,22). All samples were measured on a Macsqant Analyzer (Miltenyi Biotec) and analyzed with FlowJo software (v.8.7; FlowJo, Ashland, OR, USA).…”

Section: Splenocyte and Cardiac Mononuclear Cell Isolation And Flow Cmentioning

confidence: 99%

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Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

et al. 2018

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Regulatory T (T) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic T administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic T cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + T mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6CCCR2Cx3Cr1 monocytes and higher retention of proinflammatory Ly6CCCR2Cx3Cr1 monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + T compared with CVB3 + PBS mice. Coculture of T cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of T cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6CCCR2Cx3Cr1 subset. T-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + T compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + T mice compared with CVB3 + PBS mice. In summary, adoptive T transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Müller, I., Brandt, C., Lopez, B., González, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschöpe, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Splenocyte and Cardiac Mononuclear Cell Isolation And Flow Cmentioning

confidence: 99%

Section: Splenocyte and Cardiac Mononuclear Cell Isolation And Flow Cmentioning

confidence: 99%

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Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

et al. 2018

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The Quest for Antiinflammatory and Immunomodulatory Strategies in Heart Failure

Linthout

Tschöpe

2019

Clin Pharma and Therapeutics

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Intensive research over the last 3 decades has unequivocally demonstrated the relevance of inflammation in heart failure (HF). Despite our current and ever increasing knowledge about inflammation, the clinical success of antiinflammatory and immunomodulatory therapies in HF is still limited. This review outlines the complexity and diversity of inflammation, its reciprocal interaction with HF, and addresses future perspectives, calling for immunomodulatory therapies that are specific for factors that activate the immune system without the risk of nonspecific immune suppression.

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Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis

et al. 2022

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AimThe acute phase of a coxsackievirus 3 (CVB3)-induced myocarditis involves direct toxic cardiac effects and the systemic activation of the immune system, including the cardiosplenic axis. Consequently, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome pathway is activated, which plays a role in disease pathogenesis and progression. The anti-inflammatory drug colchicine exerts its effects, in part, via reducing NLRP3 activity, and has been shown to improve several cardiac diseases, including acute coronary syndrome and pericarditis. The aim of the present study was to evaluate the potential of colchicine to improve experimental CVB3-induced myocarditis. Methods and results C57BL6/j mice were intraperitoneally injected with 1 × 10 5 plaque forming units of CVB3. After 24 h, mice were treated with colchicine (5 μmol/kg body weight) or phosphate-buffered saline (PBS) via oral gavage (p.o.). Seven days post infection, cardiac function was haemodynamically characterized via conductance catheter measurements. Blood, the left ventricle (LV) and spleen were harvested for subsequent analyses. In vitro experiments on LV-derived fibroblasts (FB) and HL-1 cells were performed to further evaluate the anti-(fibro)inflammatory and anti-apoptotic effects of colchicine via gene expression analysis, Sirius Red assay, and flow cytometry. CVB3 + colchicine mice displayed improved LV function compared with CVB3 + PBS mice, paralleled by a 4.7-fold (P < 0.01) and 1.7-fold (P < 0.001) reduction in LV CVB3 gene expression and cardiac troponin-I levels in the serum, respectively. Evaluation of components of the NLRP3 inflammasome revealed an increased percentage of apoptosis-associated speck-like protein containing a CARD domain (ASC)-expressing, caspase-1-expressing, and interleukin-1β-expressing cells in the myocardium and in the spleen of CVB3 + PBS vs. control mice, which was reduced in CVB3 + colchicine compared with CVB3 + PBS mice. This was accompanied by 1.4-fold (P < 0.0001), 1.7fold (P < 0.0001), and 1.7-fold (P < 0.0001) lower numbers of cardiac dendritic cells, natural killer cells, and macrophages, respectively, in CVB3 + colchicine compared with CVB3 + PBS mice. A 1.9-fold (P < 0.05) and 4.6-fold (P < 0.001) reduced cardiac gene expression of the fibrotic markers, Col1a1 and lysyl oxidase, respectively, was detected in CVB3 + colchicine mice compared with CVB3 + PBS animals, and reflected by a 2.2-fold (P < 0.05) decreased Collagen I/III protein ratio. Colchicine further reduced Col3a1 mRNA and collagen protein expression in CVB3-infected FB and lowered apoptosis and viral progeny release in CVB3-infected HL-1 cells. In both CVB3 FB and HL-1 cells, colchicine down-regulated the NLRP3 inflammasome-related components ASC, caspase-1, and IL-1β. Conclusions Colchicine improves LV function in CVB3-induced myocarditis, involving a decrease in cardiac and splenic NLRP3 inflammasome activity, without exacerbation of CVB3 load.

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Mesenchymal Stromal Cells Modulate Monocytes Trafficking in Coxsackievirus B3-Induced Myocarditis

Cited by 62 publications

References 55 publications

Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

Immunomodulation by adoptive regulatory T‐cell transfer improves Coxsackievirus B3‐induced myocarditis

The Quest for Antiinflammatory and Immunomodulatory Strategies in Heart Failure

Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis

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