Pericardial Adipose Tissue Regulates Granulopoiesis, Fibrosis, and Cardiac Function After Myocardial Infarction

Horckmans, Michael; Bianchini, Mariaelvy; Santovito, Donato; Megens, Remco T. A.; Springael, Jean–Yves; Negri, Irene; Vacca, Michèle; Eusanio, Marco Di; Moschetta, Antonio; Weber, Christian; Duchêne, Johan; Steffens, Sabine

doi:10.1161/circulationaha.117.028833

Cited by 140 publications

(152 citation statements)

References 34 publications

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“…Therefore, in addition to the differences in myeloid cell recruitment described herein, differences in the number of CD4 + T cells present in a mouse strain may influence Th1/Th2 polarization and potentially cardiac remodelling post-MI [36]. Horckman et al have recently shown that removal of pericardial adipose tissue is associated with an almost 50% reduction in recruitment of neutrophils to the myocardium following MI [26]. Findings from the present study, showing that peak neutrophil infiltration of pericardial adipose tissue precedes the peak of infarct zone neutrophil count, supports the involvement of pericardial adipose tissue in regulating the infarct zone inflammatory response.…”

Section: Discussionmentioning

confidence: 85%

“…Recently it has been demonstrated that pericardial adipose tissue regulates the innate immune response in the infarcted myocardium [26]. Similar to the infarct zone, neutrophils were the predominant myeloid cell type infiltrating the pericardial adipose tissue of both C57BL/6 and BALB/c mice during the early inflammatory phase, but peaked earlier at day 1 post-MI (Fig.…”

Section: C57bl/6 Mice Show An Enhanced Inflammatory Response In the Rmentioning

confidence: 83%

“…However, cardiac rupture did not occur until later than 3 days in that study. Horckman et al have recently shown that removal of pericardial adipose tissue is associated with an almost 50% reduction in recruitment of neutrophils to the myocardium following MI [26]. In-vitro data indicate that macrophages from C57BL/6 mice intrinsically have a proinflammatory bias compared to BALB/c macrophages, as they produce more tumour necrosis factor (TNF)-α and IL-12 in response to stimulation with lipopolysaccharide [19].…”

Section: Discussionmentioning

confidence: 99%

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Enhanced monocyte recruitment and delayed alternative macrophage polarization accompanies impaired repair following myocardial infarction in C57BL/6 compared to BALB/c mice

Toor

Rückerl

Mair

et al. 2019

Clinical and Experimental Immunology

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Summary Activation of the innate immune response following myocardial infarction (MI) is essential for infarct repair. Preclinical models of MI commonly use C57BL/6 mice, which have a type 1‐dominant immune response, whereas other mouse strains such as BALB/c mice have a type 2‐dominant immune response. We compared C57BL/6 and BALB/c mice to investigate whether predisposition towards a proinflammatory phenotype influences the dynamics of the innate immune response to MI and associated infarct healing and the risk of cardiac rupture. MI was induced by permanent coronary artery ligation in 12–15‐week‐old male wild‐type BALB/c and C57BL/6 mice. Prior to MI, C57BL/6 mice had a lower proportion of CD206+ anti‐inflammatory macrophages in the heart and an expanded blood pool of proinflammatory Ly6Chigh monocytes in comparison to BALB/c mice. The systemic inflammatory response in C57BL/6 mice following MI was more pronounced, with greater peripheral blood Ly6Chigh monocytosis, splenic Ly6Chigh monocyte mobilization and myeloid cell infiltration of pericardial adipose tissue. This led to an increased and prolonged macrophage accumulation, as well as delayed transition towards anti‐inflammatory macrophage polarization in the infarct zone and surrounding tissues of C57BL/6 mice. These findings accompanied a higher rate of mortality due to cardiac rupture in C57BL/6 mice compared with BALB/c mice. We conclude that lower post‐MI survival of C57BL/6 mice over BALB/c mice is mediated in part by a more pronounced and prolonged inflammatory response. Outcomes in BALB/c mice highlight the therapeutic potential of modulating resolution of the innate immune response following MI for the benefit of successful infarct healing.

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Section: Discussionmentioning

confidence: 85%

Section: C57bl/6 Mice Show An Enhanced Inflammatory Response In the Rmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Enhanced monocyte recruitment and delayed alternative macrophage polarization accompanies impaired repair following myocardial infarction in C57BL/6 compared to BALB/c mice

Toor

Rückerl

Mair

et al. 2019

Clinical and Experimental Immunology

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“…5,9 Recent work in mice by Horckmans et al demonstrated a strong correlation between pericardial FALC B cell activation, the extent of cardiac inflammation and functional outcomes following MI. 11 Using cannabinoid receptor CB2 deficient mice (CB2 -/-) which have increased levels of circulating B cells, they concluded that secretion of Granulocyte-macrophage colony-stimulating factor (GM-CSF) by pericardial B cells promotes bone marrow granulopoiesis, cardiac neutrophil infiltration, enhances fibrosis and worsens functional cardiac outcome. 11 Furthermore, pericardial cavity macrophages have a functional phenotype comparable to other F4/80 hi serous cavity macrophage populations and are controlled by the expression of the transcription factor GATA-6.…”

Section: Introductionmentioning

confidence: 99%

“…11 Using cannabinoid receptor CB2 deficient mice (CB2 -/-) which have increased levels of circulating B cells, they concluded that secretion of Granulocyte-macrophage colony-stimulating factor (GM-CSF) by pericardial B cells promotes bone marrow granulopoiesis, cardiac neutrophil infiltration, enhances fibrosis and worsens functional cardiac outcome. 11 Furthermore, pericardial cavity macrophages have a functional phenotype comparable to other F4/80 hi serous cavity macrophage populations and are controlled by the expression of the transcription factor GATA-6. [12][13][14] Deniset et al have shown that these macrophages relocate to the injured heart where they act to suppress cardiac fibrosis.…”

Section: Introductionmentioning

confidence: 99%

The pericardium promotes cardiac repair and remodelling post-myocardial infarction

Mylonas

Jackson-Jones

Andrews

et al. 2019

Preprint

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The pericardium is widely recognised for its lubricating and bio-mechanical properties. It also contains fat-associated lymphoid clusters (FALCs) and its immune functions have been widely overlooked. Here we aimed to assess the inflammatory activity of the pericardium in patients who suffered a recent myocardial infarction (MI) and to determine its importance for repair and remodelling in a murine MI model induced by coronary artery ligation (CAL). By comparing 18 F-fluorodeoxyglucose (FDG) activity in the pericardium of patients with stable coronary artery disease and patients who had a recent MI, we demonstrate that MI is associated with increased pericardial inflammation. We confirm in mice, that pericardial FALCs undergo a major expansion following CAL. We show that despite similar initial injury, removal of the pericardium prior to MI disrupted subsequent repair, resulting in 50% mortality due to cardiac rupture, while all mice with intact pericardia survived. Removal of the pericardium also led to decreased staining for Ym1, a marker of reparative macrophages and adverse cardiac fibrosis within the infarct area. Together, this work indicates a crucial role for the pericardium in regulating inflammation, macrophage polarisation and tissue remodelling in the heart following MI.

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Irisin Promotes Cardiac Homing of Intravenously Delivered MSCs and Protects against Ischemic Heart Injury

et al. 2022

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Few intravenously administered mesenchymal stromal cells (MSCs) engraft to the injured myocardium, thereby limiting their therapeutic efficacy for the treatment of ischemic heart injury. Here, it is found that irisin pretreatment increases the cardiac homing of adipose tissue‐derived MSCs (ADSCs) administered by single and multiple intravenous injections to mice with MI/R by more than fivefold, which subsequently increases their antiapoptotic, proangiogenic, and antifibrotic effects in rats and mice that underwent MI/R. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and loss‐of‐function studies identified CSF2RB as a cytokine receptor that facilitates the chemotaxis of irisin‐treated ADSCs in the presence of CSF2, a chemokine that is significantly upregulated in the ischemic heart. Cardiac‐specific CSF2 knockdown blocked the cardiac homing and cardioprotection abilities of intravenously injected irisin‐treated ADSCs in mice subjected to MI/R. Moreover, irisin pretreatment reduced the apoptosis of hydrogen peroxide‐induced ADSCs and increased the paracrine proangiogenic effect of ADSCs. ERK1/2‐SOD2, and ERK1/2‐ANGPTL4 are responsible for the antiapoptotic and paracrine angiogenic effects of irisin‐treated ADSCs, respectively. Integrin αV/β5 is identified as the irisin receptor in ADSCs. These results provide compelling evidence that irisin pretreatment can be an effective means to optimize intravenously delivered MSCs as therapy for ischemic heart injury.

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Pericardial Adipose Tissue Regulates Granulopoiesis, Fibrosis, and Cardiac Function After Myocardial Infarction

Abstract: Our findings unveil a new mechanism by which the pericardial AT coordinates immune cell activation, granulopoiesis, and outcome after MI.

Cited by 140 publications

References 34 publications

Enhanced monocyte recruitment and delayed alternative macrophage polarization accompanies impaired repair following myocardial infarction in C57BL/6 compared to BALB/c mice

Enhanced monocyte recruitment and delayed alternative macrophage polarization accompanies impaired repair following myocardial infarction in C57BL/6 compared to BALB/c mice

The pericardium promotes cardiac repair and remodelling post-myocardial infarction

Irisin Promotes Cardiac Homing of Intravenously Delivered MSCs and Protects against Ischemic Heart Injury

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