Abstract
BackgroundThe inflammatory response plays a critical role in hypertension-induced cardiac remodeling. We aimed to study how interaction among inflammatory cells causes inflammatory responses in the process of hypertensive cardiac fibrosis.Methodology/Principal FindingsInfusion of angiotensin II (Ang II, 1500 ng/kg/min) in mice rapidly induced the expression of interferon γ (IFN-γ) and leukocytes infiltration into the heart. To determine the role of IFN-γ on cardiac inflammation and remodeling, both wild-type (WT) and IFN-γ-knockout (KO) mice were infused Ang II for 7 days, and were found an equal blood pressure increase. However, knockout of IFN-γ prevented Ang II-induced: 1) infiltration of macrophages and T cells into cardiac tissue; 2) expression of tumor necrosis factor α and monocyte chemoattractant protein 1 (MCP-1), and 3) cardiac fibrosis, including the expression of α-smooth muscle actin and collagen I (all p<0.05). Cultured T cells or macrophages alone expressed very low level of IFN-γ, however, co-culture of T cells and macrophages increased IFN-γ expression by 19.8±0.95 folds (vs. WT macrophage, p<0.001) and 20.9 ± 2.09 folds (vs. WT T cells, p<0.001). In vitro co-culture studies using T cells and macrophages from WT or IFN-γ KO mice demonstrated that T cells were primary source for IFN-γ production. Co-culture of WT macrophages with WT T cells, but not with IFN-γ-knockout T cells, increased IFN-γ production (p<0.01). Moreover, IFN-γ produced by T cells amplified MCP-1 expression in macrophages and stimulated macrophage migration.Conclusions/SignificanceReciprocal interaction between macrophages and T cells in heart stimulates IFN-γ expression, leading to increased MCP-1 expression in macrophages, which results a forward-feed recruitment of macrophages, thus contributing to Ang II-induced cardiac inflammation and fibrosis.
Highlights
Hypertension is a multi-factorial chronic inflammatory disease
We aimed to study the role of interaction between T cells and macrophages in regulating inflammatory responses in cardiac inflammation and fibrosis induced by angiotensin II (Ang II) infusion
IFN-c Expression Is Increased in Ang II-infused Hearts We have reported previously that Ang II infusion stimulates cardiac inflammation and fibrosis [14,15,16], we assessed whether IFN-c is expressed in the process of Ang II-induced hypertensive cardiac inflammation and fibrosis
Summary
Hypertension is a multi-factorial chronic inflammatory disease. It induces cardiac remodeling, which is characterized by inflammation, fibrosis and hypertrophy, a major cause of heart failure. In hypertension stage, damaged vasculature release inflammatory signals to recruit leukocytes into cardiac tissues, and initiate fibrosis cascade [1]. The interaction between these inflammatory cells is complex and is still largely unknown. Several studies point to a role for the immune system in Ang II– dependent hypertension and its complications. The inflammatory response plays a critical role in hypertension-induced cardiac remodeling. We aimed to study how interaction among inflammatory cells causes inflammatory responses in the process of hypertensive cardiac fibrosis
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