Immunological aspect of cardiac remodeling: T lymphocyte subsets in inflammation-mediated cardiac fibrosis

Abstract

Cardiac fibrosis is defined as a progressive accumulation of fibrillar extracellular matrix (ECM) in the myocardium. The regulation of extracellular matrix remodeling is primarily mediated by cardiac fibroblasts (CF). Evidences suggest that various T lymphocyte phenotypes differentially affect organ fibrosis through modulating CF collagen and MMP/TIMP gene expression, MMP activity and cardiac collagen cross-linking, leading to altered ECM composition. In regard to the importance of cytokines in cardiac fibrosis and heart failure, in this review, we will address the role of different T cell subsets in inflammation-mediated cardiac fibrosis, from a distinct perspective of T cell and fibroblast interaction. We conclude that in addition to preventive strategies, therapies based on deviation of Th1/Th2 paradigm, and manipulation of Tregs and Th17 would show promising results in future studies.

Introduction

Chronic heart failure is a progressive syndrome and the outcome of a variety of cardiovascular diseases. It is one of the main public health problems that result in a poor life quality and place an economic burden on the health care system worldwide. Regardless of its pathogenesis, heart failure progression is mainly caused by left ventricle remodeling. Therefore, investigation of the mechanisms underlying the common basis of heart failure, i.e., cardiac remodeling, would provide an important breakthrough. The pathologic changes in heart failure occur in 2 steps: one is cardiomyocyte hypertrophy, necrosis, and apoptosis, and the other is cardiac fibroblasts hyperplasia and cardiac fibrosis. Most of the recent studies on cardiac function are focused on the prevention and reversion of structurally and functionally abnormal cardiomyocytes, since the importance of cardiac fibrosis in the pathogenesis of heart failure has been recognized (Quercioli et al., 2010, Chen and Frangogiannis, 2010, Shvu et al., 2010). Cardiac fibrosis has now become the new target for heart failure therapy (Zhang and Xu, 2006).

Cardiac fibrosis is defined as a progressive accumulation of fibrillar extracellular matrix (ECM) in the myocardium. The regulation of ECM remodeling is primarily mediated by cardiac fibroblast (CF) cells, which are the main nonmuscle cells in the heart. CFs modulate matrix turnover in nonpathological conditions, and their activity is greatly enhanced after an acute cardiac event or during chronic cardiovascular disease (Olson et al., 2008, Yu et al., 2005). CF abnormality leads to overaccumulation of ECM, significantly elevated concentrations of fibrillar collagen, or uncontrolled cross-linking of collagen molecules. These changes occur as a wound healing response to chronic cardiac injury due to myocardial infarction, pressure overload (hypertension, aortic stenosis, etc.), inflammatory response (myocarditis and dilated cardiomyopathy), exposure to toxic agents (alcohol and toxicity), or volume overload (valvular regurgitation and congenital heart diseases), which may eventually result in cardiac remodeling and heart failure. ECM remodeling is critical for proper development and repair of the tissue, and faulty remodeling results in tissue fibrosis (Shi et al., 1997).

Lymphocytes modulate fibroblast collagen formation during the healing of noncardiac tissues such as pulmonary, hepatic, etc. (Chizzolini et al., 2003, Mauri et al., 2003, Chiaramonte et al., 1999). T lymphocytes might control the fibrogenic process by directly interacting with myofibroblasts or fibroblasts and by secreting cytokines that participate in wound healing (Wynn, 2008). T lymphocyte infiltration after myocardial infarction coincides with increased cardiac fibroblast proliferation and enhanced fibrotic function (Yang et al., 2002), and the former has been associated with the notion that lymphocytes are essential for wound healing in the heart (Barbul and Regan, 1990, Barbul and Regan, 1995). Therefore, it can be speculated that T lymphocytes and fibroblasts function synergically in cardiac remodeling after tissue injury. However, it is unclear how such interaction occurs during myocarditis that is characterized by cardiac fibrosis (Frizelle et al., 1992, Leslie et al., 1990), and few clarifications are available thus far. The pathogenesis of chronic inflammatory diseases, such as myocarditis, is assumed to depend on the interaction between activated T cells and resident tissue cells or migratory cells (fibroblasts) (Frizelle et al., 1992, Leslie et al., 1990, Schmidt-Weber et al., 2007). The outcome of fibrosis, at least in part, is influenced by such an interaction.

To date, 4 main T cell populations have been reported to develop from naïve CD4+ T lymphocytes. T cells differentiate through distinct pathways after activation and acquire specialized properties and effector functions. Conventionally, T helper cells are thought to develop into Th1 and Th2 cell subsets; Th1 cells enhance the eradication of intracellular pathogens (by producing interferon-γ, IFN-γ) and the Th2 cell lineage is important for enhancing the elimination of extracellular organisms (by producing interleukin (IL)-4, IL-5, and IL-13). A recent study suggests that a subset of IL-17-producing cells, distinct from the Th1 or Th2 cells, plays a critical role in inducing inflammatory tissue injury. Further, CD4+CD25+Foxp3+ regulatory T cells (Tregs) are known as the regulators of effector responses and these cells can down-modulate autoimmune responses and protect against inflammatory tissue injury. It has been hypothesized that the same precursor can be induced to differentiate into either Th1 or Th2 population, similar to the differentiation of Th17 and Tregs (Zhu et al., 2010). In this article, we have summarized the reported evidences of the involvement of different T lymphocyte subsets in the fibrogenic processes, especially those that occur in the heart.