Immune repertoires in the failing heart: the global picture (original) (raw)
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Journal of Molecular and Cellular Cardiology, 2019
Pressure overload-induced cardiac hypertrophy and remodeling are not simply mechanical responses to overloaded stress. They also involve participation of various immune cells, especially T cells. In this review, we summarized recent advances in understanding the roles of T cells in this process and the possible mechanisms underlying T cells involvement and modulation. In this pathological process, αβT cells play an indispensable role, with contribution of NKT cells and γδT cells. Moreover, among the αβT cells, CD4+ T cells rather than CD8+ T cells are dominant in the process with different subsets exerting diverse influences. Th1 and Th17 cells mainly promote the pathological development, while Treg cells are negative modulators that alleviate cardiac hypertrophy and remodeling. Even though the involvement of T cells has been reported extensively, the detailed modulating mechanism remains to be elucidated. Pressure overload exerting on heart stimulates cytokines secretion from resident cardiac cells and upregulates cell adhesion molecules on cardiac endothelial cells, which together might mediate T cells infiltration into the heart. Infiltrating T cells modulate pro-hypertrophic pathways and the transition from cardiac fibroblasts to myofibroblasts, which might represent mechanisms underlying their effects. Considering the vital participation of T cells, immune regulation
The Regulatory Role of T Cell Responses in Cardiac Remodeling Following Myocardial Infarction
International Journal of Molecular Sciences
Ischemic injury to the heart causes cardiomyocyte and supportive tissue death that result in adverse remodeling and formation of scar tissue at the site of injury. The dying cardiac tissue secretes a variety of cytokines and chemokines that trigger an inflammatory response and elicit the recruitment and activation of cardiac immune cells to the injury site. Cell-based therapies for cardiac repair have enhanced cardiac function in the injured myocardium, but the mechanisms remain debatable. In this review, we will focus on the interactions between the adoptively transferred stem cells and the post-ischemic environment, including the active components of the immune/inflammatory response that can mediate cardiac outcome after ischemic injury. In particular, we highlight how the adaptive immune cell response can mediate tissue repair following cardiac injury. Several cell-based studies have reported an increase in pro-reparative T cell subsets after stem cell transplantation. Paracrine ...
The Role of Interleukin-1 in the Failing Heart
Developments in Cardiovascular Medicine, 2001
The prevalance of congestive heart failure and its continued poor prognosis despite presently available therapeutic options emphasize the importance of pursuing the observations suggesting an important role for an immunomodulatory approach to decompensated cardiac failure. Furthermore, there are several pieces of background information that suggest that cytokines like IL-1 may play a signi®cant role in the pathogenesis of several forms of myocardial dysfunction. Although it seems clear that IL-1 is not acting alone under circumstances of myocardial injury, but in concert with other pro-in¯ammatory molecules and their effectors, we believe that continued investigations into the cytokine hypothesis will ultimately increase the understanding of how pro-in¯ammatory molecules in¯uence myocardial function and how the modulation of such factors may improve the myocardial response to injury. The speci®c observations that emphasize the importance of pursuing a substantive role for IL-1 in this process are: (1) IL-1 is elevated in several cardiac disease states, (2) IL-1 is produced by myocardial cells themselves in response to injury, (3) The alterations in gene expression seen in response IL-1 resembles in many ways the phenotype of the failing heart, and (4) The co-localization of the IL-1 response with that of several previously described negative transcriptional regulators (making them potential targets for therapeutic manipulation).
Cytokine, 2019
This study was aimed to elucidate the immunoregulatory properties of human cardiac fibroblasts cultured under pro-inflammatory and hypoxic conditions. Human heart tissue for isolating cardiac cells is generally hard to obtain, particularly from all four chambers of the same heart. Since different parts of the heart have different functions and therefore may have different immunoregulatory properties, ability to analyse cells from all chambers allows for a unique and comprehensive investigation. Cells were isolated from all four chambers of the heart from patients undergoing cardiac transplantation surgery due to severe chronic heart failure (CHF) (n = 6). Cells isolated from one donor heart, were used for comparison with the experimental group. Primary cultured human cardiac fibroblasts were treated with Lipopolysaccharide (LPS) to induce an inflammatory response. Cells were also subjected to hypoxia. To determine immunoregulatory properties of the cells, cytokine and chemokine profiles were determined using multiplex ELISA. Results: On average, the fibroblasts population constituted approximately 90% of the expanded non-myocytes. Levels of cytokines and chemokines were markedly increased in human cardiac fibroblasts cultured under inflammatory conditions, with a similar response in fibroblasts from all compartments of the heart. Unexpectedly, hypoxia did not further augment cytokine and chemokine secretion. In conclusion, human cardiac fibroblasts are a robust source of pro-inflammatory mediators in the failing heart, independent of hypoxia, and might play a critical role in inflammation associated with the pathogenesis of CHF.
T cell costimulation blockade blunts pressure overload-induced heart failure
Nature communications, 2017
Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results s...
Role of Inflammation in Cardiac Remodeling After Acute Myocardial Infarction
Frontiers in Physiology
Atherosclerosis is defined as an inflammatory disease. Low-grade inflammation is present in all phases of the cardiovascular continuum, since the establishment of cardiovascular risk factors and ischemic heart disease until cardiovascular events, such as myocardial infarction, heart failure and death. Not all inflammatory pathways are linked to cardiovascular outcomes, and thus, not all anti-inflammatory approaches decrease cardiovascular events. The most common cause of ventricular remodeling and heart failure is ischemic heart disease. Biomarkers such as high-sensitivity C-reactive protein can identify individuals at risk of major cardiovascular complications, but this biomarker has no causal effect on cardiovascular disease. On the other hand, interleukin 6 appears to be causally associated with cardiovascular disease. CANTOS was the first proof of concept study showing that anti-inflammatory therapy reduces major cardiovascular outcomes. Based on many anti-inflammatory trials, o...
Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses
Journal of Clinical Investigation
T cell autoreactivity is a hallmark of autoimmune diseases but can also benefit self-maintenance and foster tissue repair. Herein, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of myocardial infarction (MI), the leading cause of death worldwide. After screening more than 150 class-II-restricted epitopes, we found that myosin heavy chain alpha (MYHCA) was a dominant cardiac antigen triggering post-MI CD4 + T cell activation in mice. Transferred MYHCA614-629-specific CD4 + T (TCR-M) cells selectively accumulated in the myocardium and mediastinal lymph nodes (med-LN) of infarcted mice, acquired a Treg phenotype with a distinct pro-healing gene expression profile, and mediated cardioprotection. Myocardial Treg cells were also detected in autopsies from patients who suffered a MI. Noninvasive PET/CT imaging using a CXCR4 radioligand revealed enlarged med-LNs with increased cellularity in MI-patients. Notably, the med-LN alterations observed in MI patients correlated with the infarct size and cardiac function. Taken together, the results obtained in our study provide evidence showing that MI-context induces pro-healing T cell autoimmunity in mice and confirms the existence of an analogous heart/med-LN/T cell axis in MI patients.
Cardiovascular Research
Cardiac injury may have multiple causes, including ischaemic, non-ischaemic, autoimmune, and infectious triggers. Independent of the underlying pathophysiology, cardiac tissue damage induces an inflammatory response to initiate repair processes. Immune cells are recruited to the heart to remove dead cardiomyocytes, which is essential for cardiac healing. Insufficient clearance of dying cardiomyocytes after myocardial infarction (MI) has been shown to promote unfavourable cardiac remodelling, which may result in heart failure (HF). Although immune cells are integral key players of cardiac healing, an unbalanced or unresolved immune reaction aggravates tissue damage that triggers maladaptive remodelling and HF. Neutrophils and macrophages are involved in both, inflammatory as well as reparative processes. Stimulating the resolution of cardiac inflammation seems to be an attractive therapeutic strategy to prevent adverse remodelling. Along with numerous experimental studies, the promis...
Brazilian journal of medical and biological research = Revista brasileira de pesquisas médicas e biológicas / Sociedade Brasileira de Biofísica ... [et al.], 2010
After myocardial infarction (MI), activation of the immune system and inflammatory mechanisms, among others, can lead to ventricular remodeling and heart failure (HF). The interaction between these systemic alterations and corresponding changes in the heart has not been extensively examined in the setting of chronic ischemia. The main purpose of this study was to investigate alterations in cardiac gene and systemic cytokine profile in mice with post-ischemic HF. Plasma was tested for IgM and IgG anti-heart reactive repertoire and inflammatory cytokines. Heart samples were assayed for gene expression by analyzing hybridization to AECOM 32k mouse microarrays. Ischemic HF significantly increased the levels of total serum IgM (by 5.2-fold) and total IgG (by 3.6-fold) associated with a relatively high content of anti-heart specificity. A comparable increase was observed in the levels of circulating pro-inflammatory cytokines such as IL-1beta (3.8X) and TNF-alpha (6.0X). IFN-gamma was als...
Role of Lymphocytes in Myocardial Injury, Healing, and Remodeling After Myocardial Infarction
Circulation research, 2015
A large body of evidence produced during decades of research indicates that myocardial injury activates innate immunity. On the one hand, innate immunity both aggravates ischemic injury and impedes remodeling after myocardial infarction (MI). On the other hand, innate immunity activation contributes to myocardial healing, as exemplified by monocytes' central role in the formation of a stable scar and protection against intraventricular thrombi after acute infarction. Although innate leukocytes can recognize a wide array of self-antigens via pattern recognition receptors, adaptive immunity activation requires highly specific cooperation between antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. We have only recently begun to examine lymphocyte activation's relationship to adaptive immunity and significance in the context of ischemic myocardial injury. There is some experimental evidence that CD4(+) T-cells contribute to ischemia-reperfusion injur...