Dataset Information

Neutrophil inhibition improves acute inflammation in a murine model of viral myocarditis.

ABSTRACT:

Aims

Viral myocarditis (VM) is an inflammatory pathology of the myocardium triggered by a viral infection that may cause sudden death or heart failure (HF), especially in the younger population. Current treatments only stabilize and improve cardiac function without resolving the underlying inflammatory cause. The factors that induce VM to progress to HF are still uncertain, but neutrophils have been increasingly associated with the negative evolution of cardiac pathologies. The present study investigates the contribution of neutrophils to VM disease progression in different ways.

Methods and results

In a coxsackievirus B3- (CVB3) induced mouse model of VM, neutrophils and neutrophil extracellular traps (NETs) were prominent in the acute phase of VM as revealed by enzyme-linked immunosorbent assay analysis and immunostaining. Anti-Ly6G-mediated neutrophil blockade starting at model induction decreased cardiac necrosis and leucocyte infiltration, preventing monocyte and Ly6CHigh pro-inflammatory macrophage recruitment. Furthermore, genetic peptidylarginine deiminase 4-dependent NET blockade reduced cardiac damage and leucocyte recruitment, significantly decreasing cardiac monocyte and macrophage presence. Depleting neutrophils with anti-Ly6G antibodies at 7 days post-infection, after the acute phase, did not decrease cardiac inflammation.

Conclusion

Collectively, these results indicate that the repression of neutrophils and the related NET response in the acute phase of VM improves the pathological phenotype by reducing cardiac inflammation.

SUBMITTER: Carai P

PROVIDER: S-EPMC9847559 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Neutrophil inhibition improves acute inflammation in a murine model of viral myocarditis.

Carai Paolo P González Laura Florit LF Van Bruggen Stijn S Spalart Valerie V De Giorgio Daria D Geuens Nadéche N Martinod Kimberly K Jones Elizabeth Anne Vincent EAV Heymans Stephane S

Cardiovascular research 20230101 17

<h4>Aims</h4>Viral myocarditis (VM) is an inflammatory pathology of the myocardium triggered by a viral infection that may cause sudden death or heart failure (HF), especially in the younger population. Current treatments only stabilize and improve cardiac function without resolving the underlying inflammatory cause. The factors that induce VM to progress to HF are still uncertain, but neutrophils have been increasingly associated with the negative evolution of cardiac pathologies. The present s ...[more]

PMID: 35426438

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Project description:ObjectiveAcute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis.ResultsHere we present the discovery of a novel endogenous T2* MRI contrast of myocardial lesions in murine models of acute and chronic CVB3 myocarditis. The evaluation of infected hearts ex vivo and in vivo by 3D T2w and T2*w MRI allowed direct localization of virus-induced myocardial lesions without any MRI tracer or contrast agent. T2*w weighted MRI is able to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was confirmed by spatial correlation of MRI hypointensity in myocardium with myocardial lesions histologically. Additional in vivo and ex vivo MRI analysis proved that the contrast mechanism was due to a strong paramagnetic tissue alteration in the vicinity of myocardial lesions, effectively pointing towards iron deposits as the primary contributor of contrast. The evaluation of the biological origin of the MR contrast by specific histological staining and transmission electron microscopy revealed that impaired iron metabolism primarily in mitochondria caused iron deposits within necrotic myocytes, which induces strong magnetic susceptibility in myocardial lesions and results in strong T2* contrast.ConclusionThis T2*w MRI technique provides a fast and sensitive diagnostic tool to determine the patterns and the severity of acute and chronic enteroviral myocarditis and the precise localization of tissue damage free of MR contrast agents.

Project description:Background Lung injury, a severe adverse outcome of lipopolysaccharide-induced acute respiratory distress syndrome, is attributed to excessive neutrophil recruitment and effector response. Poldip2 (polymerase δ-interacting protein 2) plays a critical role in regulating endothelial permeability and leukocyte recruitment in acute inflammation. Thus, we hypothesized that myeloid Poldip2 is involved in neutrophil recruitment to inflamed lungs. Methods and Results After characterizing myeloid-specific Poldip2 knockout mice, we showed that at 18 hours post-lipopolysaccharide injection, bronchoalveolar lavage from myeloid Poldip2-deficient mice contained fewer inflammatory cells (8 [4-16] versus 29 [12-57]×104/mL in wild-type mice) and a smaller percentage of neutrophils (30% [28%-34%] versus 38% [33%-41%] in wild-type mice), while the main chemoattractants for neutrophils remained unaffected. In vitro, Poldip2-deficient neutrophils responded as well as wild-type neutrophils to inflammatory stimuli with respect to neutrophil extracellular trap formation, reactive oxygen species production, and induction of cytokines. However, neutrophil adherence to a tumor necrosis factor-α stimulated endothelial monolayer was inhibited by Poldip2 depletion (225 [115-272] wild-type [myePoldip2+/+] versus 133 [62-178] myeloid-specific Poldip2 knockout [myePoldip2-/-] neutrophils) as was transmigration (1.7 [1.3-2.1] versus 1.1 [1.0-1.4] relative to baseline transmigration). To determine the underlying mechanism, we examined the surface expression of β2-integrin, its binding to soluble intercellular adhesion molecule 1, and Pyk2 phosphorylation. Surface expression of β2-integrins was not affected by Poldip2 deletion, whereas β2-integrins and Pyk2 were less activated in Poldip2-deficient neutrophils. Conclusions These results suggest that myeloid Poldip2 is involved in β2-integrin activation during the inflammatory response, which in turn mediates neutrophil-to-endothelium adhesion in lipopolysaccharide-induced acute respiratory distress syndrome.

Dataset Information

Neutrophil inhibition improves acute inflammation in a murine model of viral myocarditis.

Aims

Methods and results

Conclusion

Publications

Neutrophil inhibition improves acute inflammation in a murine model of viral myocarditis.

Similar Datasets

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