The heart under pressure: immune cells in fibrotic remodeling

Theall, Brandon P.; Alcaide, Pilar

doi:10.1016/j.cophys.2022.100484

Cited by 6 publications

(5 citation statements)

References 60 publications

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“…37,38 While we did not explicitly test this, it is possible that in a more complex scenario in vivo, DAMP agonism of TLRs in Th1 cells among other cells also contributes to cardiac fibrosis and inflammation, in line with studies reporting that DAMP sensing by CFB can contribute to fibrosis. 39,40 More work in the field is warranted to investigate potential cross talk between TLR/DAMP receptors and TCR signals through MyD88 or other adaptors in distinct inflammatory and infectious settings.…”

Section: Discussionmentioning

confidence: 99%

T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation

Bayer

Smolgovsky

Ngwenyama

et al. 2023

Circulation Research

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BACKGROUND: Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown. METHODS: We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled WT versus Myd88 −/− mouse T cells at the transcript and protein level and performed several functional assays. RESULTS: Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated Myd88 −/− T cells had increased proinflammatory signaling at the transcript and protein level compared with WT, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling. CONCLUSIONS: Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress.

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Section: Discussionmentioning

confidence: 99%

T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation

Bayer

Smolgovsky

Ngwenyama

et al. 2023

Circulation Research

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“…Precise stratification of patients and individualising therapies considering patients’ heterogeneous would be the future direction ( 91 , 92 ). Numerous studies have demonstrated that the cardiac immune cell fractions is associated with the mechanism of fibrosis in patients ( 93 , 94 ). Here, we developed a novel patient stratifying method based on the immune cell fractions and demonstrated the potential of this stratifying method in predicting patients’ fibrotic mechanisms and assisting the design of drug treatments.…”

Section: Discussionmentioning

confidence: 99%

Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure

Zou

Khoo²

2023

Front. Immunol.

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BackgroundA central issue hindering the development of effective anti-fibrosis drugs for heart failure is the unclear interrelationship between fibrosis and the immune cells. This study aims at providing precise subtyping of heart failure based on immune cell fractions, elaborating their differences in fibrotic mechanisms, and proposing a biomarker panel for evaluating intrinsic features of patients’ physiological statuses through subtype classification, thereby promoting the precision medicine for cardiac fibrosis.MethodsWe inferred immune cell type abundance of the ventricular samples by a computational method (CIBERSORTx) based on ventricular tissue samples from 103 patients with heart failure, and applied K-means clustering to divide patients into two subtypes based on their immune cell type abundance. We also designed a novel analytic strategy: Large-Scale Functional Score and Association Analysis (LAFSAA), to study fibrotic mechanisms in the two subtypes.ResultsTwo subtypes of immune cell fractions: pro-inflammatory and pro-remodeling subtypes, were identified. LAFSAA identified 11 subtype-specific pro-fibrotic functional gene sets as the basis for personalised targeted treatments. Based on feature selection, a 30-gene biomarker panel (ImmunCard30) established for diagnosing patient subtypes achieved high classification performance, with the area under the receiver operator characteristic curve corresponding to 0.954 and 0.803 for the discovery and validation sets, respectively.ConclusionPatients with the two subtypes of cardiac immune cell fractions were likely having different fibrotic mechanisms. Patients’ subtypes can be predicted based on the ImmunCard30 biomarker panel. We envision that our unique stratification strategy revealed in this study will unravel advance diagnostic techniques for personalised anti-fibrotic therapy.

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“…Although medications used to treat pulmonary fibrosis, such as pirfenidone, show an ability to decrease cardiac fibrosis, they result in minimal improvement in diastolic function [95]. As a subset of lymphocytes, regulatory T cells (Tregs) have demonstrated remarkable anti-inflammatory and cardioprotective properties [5,[96][97]. Many studies have shown its role as an immune regulator of unwanted immune responses as well as a regulator of pro-inflammatory T cells [98].…”

Section: Immune Cell Therapymentioning

confidence: 99%

Inflammatory Causes and Immunotherapy Potential in Cardiovascular Diseases Treatment

2023

Cardiolog Res Cardiovasc Med

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Inflammatory profile in the cardiovascular diseases has been acknowledged widely; yet the potential of immunotherapy in the treatment of cardiovascular diseases (CVD) is not fully met. The primary and secondary inflammatory risk factors of CVD; as well as drivers of atherosclerosis from the immune system are elaborated in this review. The approaches to treat CVD in respect of immunotherapy focus on targeting cytokine response pathways; novel engineering cytokines and superkines; and targeting specialized pro-resolving mediators (SPMs) in atherosclerosis. Immunotherapy in the treatment of heart failure has gained great advancement in targeting heart fibrosis to stop and even reverse cardiac remodeling. With a deeper understanding of the roles T cells and macrophages in the development of fibrosis in heart failure; harnessing them became possible to treat heart failure. T-cell therapy with chimeric antigen receptor (CAR T-cell); as well as CRISPR gene editing therapy make personalized diagnosis and treatment possible and bring a lot of hope to concur this debilitating disease. This review attempts to summarize new understandings of inflammatory mechanisms underlying CVD and major advancements as well as challenges in CVD immunotherapy with a hope to offer a perspective on strategies to advance future therapies.

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The heart under pressure: immune cells in fibrotic remodeling

Cited by 6 publications

References 60 publications

T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation

T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation

Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure

Inflammatory Causes and Immunotherapy Potential in Cardiovascular Diseases Treatment

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