Human cardiac fibroblasts isolated from patients with severe heart failure are immune-competent cells mediating an inflammatory response

Sandstedt, Joakim; Sandstedt, Mikael; Lundqvist, Annika; Jansson, Maria; Sopasakis, Victoria Rotter; Jeppsson, Anders; Hultén, Lillemor Mattsson

doi:10.1016/j.cyto.2018.09.021

Cited by 19 publications

(18 citation statements)

References 29 publications

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“…Similar to macrophages, cardiac fibroblasts assume an inflammatory role by secreting immune cell-recruiting cytokines and chemokines 52 and assume a phagocytic role 53 suggesting phenotype plasticity and cell switching in the setting of myocardial injury.…”

Section: Discussionmentioning

confidence: 99%

Identification of CD4⁺ Sub-population of Resident Cardiac Fibroblasts Linked to Myocardial Fibrosis

Siamwala

Pagano

Dubielecka

et al. 2021

Preprint

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Background: Infiltration with inflammatory CD4+ T-cells and the accumulation of heterogeneous cardiac myofibroblasts are hallmarks of cardiac fibrosis and remodeling. The origin, identity, states, and functions of the resident cells involved in the transition from adaptive to maladaptive fibrotic remodeling, as well as the pathways of inflammatory regulation are unclear. Methods: We performed mass cytometry profiling of resident human ventricular cardiac fibroblasts (hVCF) and determined the identity of cells contained in fibrotic right ventricle autopsy tissues from individuals diagnosed with pulmonary hypertension and tissue from SUGEN/hypoxia rats exhibiting cardiac fibrosis. We further characterized the resident cardiac fibroblast sub-population morphologically, structurally and functionally using transcriptome and secretome analysis of the secreted cytokines, chemokines, proteins, metabolites using milliplex panels, proteomics and metabolomics pipelines. Results: Single-cell mass cytometry identified remarkable plasticity of resident human cardiac fibroblasts. We provide evidence of a sub-population of resident cardiac myofibroblasts expressing high levels of CD4+, a helper T-cell surface marker in addition to mesenchymal markers, αSMA and Vimentin in all the human donors. These cardiac cells co-expressing lymphoid CD4+and αSMA+ were localized to the fibrotic regions of the human right ventricular tissue and were a common feature in the interstitial and perivascular lesions of SUGEN/Hypoxia (SuHx) rats. CD3+CD4+ T-cell numbers were higher in the right ventricle compared with the left ventricle of SuHx, as determined by flow cytometry. In vitro, T-cell homing receptors CD44, Interleukin-1 receptor (IL-1R), and CCR2 were upregulated in cardiac fibroblasts in response to IL-1β. Exposure of cardiac fibroblasts to IL-1β led to upregulation of genes regulating extracellular matrix, collagen deposition and inflammation-related genes, and induced secretion of cytokines, chemokines, and metabolites involved in innate and adaptive humoral immune responses. Cell clustering, elevated phosphorylation of MAPK p38 and inflammatory NF-κB p65 and cell phenotype switching upon IL-1β stimulation reverted with the administration of an IL-1R antagonist. Conclusions: Our data expand concepts of heterogeneity of resident cardiac fibroblasts and plasticity in response to pro-inflammatory cytokines by the demonstration of a unique subpopulation of cardiac fibroblasts exhibiting attributes of both mesenchymal and lymphoid cells. Exposure of cardiac fibroblasts to the pro-inflammatory cytokine, IL-1β, induces a robust phenotypic response linked to extracellular matrix deposition and up-regulates an immune-associated phenotype linked to expression of immune markers and secretion of immunomodulatory cytokines and chemokines. We also propose that resident cardiac fibroblast transdifferentiation and phenotype switching maybe the key process involved in adaptive to maladaptive remodeling leading to fibrosis and failure. Non-standard abbreviations: CD4; Cluster of differentiation, αSMA; alpha smooth muscle actin, IL-1R; Interleukin-1-receptor, CCR2; C-X-C Motif Chemokine Receptor 2

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Section: Discussionmentioning

confidence: 99%

Identification of CD4⁺ Sub-population of Resident Cardiac Fibroblasts Linked to Myocardial Fibrosis

Siamwala

Pagano

Dubielecka

et al. 2021

Preprint

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“…In addition, lymphocytes and monocytes can lead to the expression of beta-adrenergic receptors, and beta-adrenergic stimulation can modulate cytokine production by these cells [42,43]. Recently, it has been established that myocardial fibroblasts in people with severe heart failure are able to synthesize pro-inflammatory cytokines [44,45]. In addition, it has been found that the expression of myocardial receptors for serotonin type 2B is associated with myocardial remodeling and cytokine synthesis in dogs with dilated cardiomyopathy [10].…”

Section: Discussionmentioning

confidence: 99%

Immune-inflammatory concept of the pathogenesis of chronic heart failure in dogs with dilated cardiomyopathy

et al. 2019

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Background: Dilated cardiomyopathy is common in dogs. This form of cardiomyopathy is the main cause of death due to heart disease in dogs. Death can occur suddenly in clinically normal animals as a result of the progression of congestive heart failure (CHF). The pathogenesis of heart failure syndrome in dogs with dilated cardiomyopathy involves activation of the neurohumoral system and immune-mediated inflammation, which leads to further progression of the condition. Heart failure syndrome in dogs with dilated cardiomyopathy is caused by the progressive loss of cardiomyocytes, apoptosis, remodeling of the left ventricle, systolic and diastolic dysfunction, arrhythmias, reduced cerebral blood flow, the involvement of other key internal organs, and intestinal dysbiosis. Aim: This study aimed to determine the immunological and inflammatory mechanisms surrounding the development of heart failure syndrome in dogs with dilated cardiomyopathy. Materials and Methods: The subjects of this study were dogs with a dilated form of cardiomyopathy (n=159), complicated by various functional classes of heart failure syndrome. Evaluation of myocardial remodeling, systolic function, and systemic hemodynamics was performed using EMP-860 Vet and PU-2200V ultrasound scanners according to the standard technique. Electrocardiography was performed with all dogs in right lateral recumbency using the EK1T-04 Midas electrocardiograph (50 mm/s speed and 1 mV gain = 1 cm). Results: In some affected animals, especially in cases of compensated dilated cardiomyopathy, leukocytosis was noted. In patients with dilated cardiomyopathy complicated by heart failure syndrome of various functional classes, the number of neutrophils was significantly increased, and the number of lymphocytes was decreased by 1.9-2.1 times when compared with those in clinically normal animals. In dogs with dilated cardiomyopathy, neutrophilic leukocytosis develops with a simple regenerative shift to the left. The results of immunological studies indicate that dogs with dilated cardiomyopathy develop T lymphocytopenia as compared with clinically normal animals. Conclusion: The central component of heart failure syndrome in dogs with dilated cardiomyopathy is the activation of the neurohumoral system and immune-mediated inflammation. The development of CHF in dogs with dilated cardiomyopathy is caused by the progressive loss of cardiomyocytes, apoptosis, remodeling of the left ventricle, systolic and diastolic dysfunction, arrhythmias, reduced cerebral blood flow, involvement of other key internal organs, and intestinal dysbiosis.

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“…Gene expression analysis of cardiac fibroblasts 1 day after MI revealed upregulation of inflammatory cytokines, such as Ccl5, and Cxcl3, coupled with a downregulation of TGFβ signaling component genes [98]. Furthermore, primary cultured cardiac fibroblasts from severe heart failure patients exhibited LPS-induced cytokine production with increased expression of CCL2, IFN, IL1β, IL6, IL8/CXCL8, and TNFα [103]. By 3 days after MI, cardiac fibroblasts transition towards proliferative and pro-angiogenic function before shifting toward a collagen and fibronectin depositing, profibrotic function 7 days after injury [104].…”

Section: Contribution Of Fibroblasts To Tissue Inflammationmentioning

confidence: 99%

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

Cooper

Haas

Noonepalle

et al. 2021

IJMS

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Irregular inflammatory responses are a major contributor to tissue dysfunction and inefficient repair. Skin has proven to be a powerful model to study mechanisms that regulate inflammation. In particular, skin wound healing is dependent on a rapid, robust immune response and subsequent dampening of inflammatory signaling. While injury-induced inflammation has historically been attributed to keratinocytes and immune cells, a vast body of evidence supports the ability of non-immune cells to coordinate inflammation in numerous tissues and diseases. In this review, we concentrate on the active participation of tissue-resident adipocytes and fibroblasts in pro-inflammatory signaling after injury, and how altered cellular communication from these cells can contribute to irregular inflammation associated with aberrant wound healing. Furthering our understanding of how tissue-resident mesenchymal cells contribute to inflammation will likely reveal new targets that can be manipulated to regulate inflammation and repair.

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Human cardiac fibroblasts isolated from patients with severe heart failure are immune-competent cells mediating an inflammatory response

Cited by 19 publications

References 29 publications

Identification of CD4⁺ Sub-population of Resident Cardiac Fibroblasts Linked to Myocardial Fibrosis

Identification of CD4⁺ Sub-population of Resident Cardiac Fibroblasts Linked to Myocardial Fibrosis

Immune-inflammatory concept of the pathogenesis of chronic heart failure in dogs with dilated cardiomyopathy

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

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Human cardiac fibroblasts isolated from patients with severe heart failure are immune-competent cells mediating an inflammatory response

Cited by 19 publications

References 29 publications

Identification of CD4+ Sub-population of Resident Cardiac Fibroblasts Linked to Myocardial Fibrosis

Identification of CD4+ Sub-population of Resident Cardiac Fibroblasts Linked to Myocardial Fibrosis

Immune-inflammatory concept of the pathogenesis of chronic heart failure in dogs with dilated cardiomyopathy

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

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Product

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Identification of CD4⁺ Sub-population of Resident Cardiac Fibroblasts Linked to Myocardial Fibrosis

Identification of CD4⁺ Sub-population of Resident Cardiac Fibroblasts Linked to Myocardial Fibrosis