CCR5 Signaling Suppresses Inflammation and Reduces Adverse Remodeling of the Infarcted Heart, Mediating Recruitment of Regulatory T Cells

Abstract

Myocardial infarction triggers an inflammatory reaction that is involved in cardiac remodeling. Cardiac repair is dependent on regulatory mechanisms that suppress inflammation and prevent excessive matrix degradation. Chemokine induction in the infarcted heart mediates recruitment of leukocyte subsets with distinct properties. We demonstrate that signaling through the CC chemokine receptor 5 (CCR5) prevents uncontrolled postinfarction inflammation and protects from adverse remodeling by recruiting suppressive mononuclear cells. CCR5 and its ligands macrophage inflammatory protein (MIP)؊1␣ and MIP-1␤ were markedly induced in the infarcted mouse myocardium. In addition, almost 40% of the mononuclear cells infiltrating the infarct expressed CCR5. CCR5؊/؊ mice exhibited marked upregulation of proinflammatory cytokine and chemokine expression in the infarct. In wildtype infarcts CCR5؉ mononuclear cells had antiinflammatory properties, expressing higher levels of IL-10 than CCR5 ؊ cells. In contrast, mononuclear cells isolated from CCR5 ؊/؊ infarcts had reduced IL-10 expression. Moreover, enhanced inflammation in the absence of CCR5 was associated with impaired recruitment of CD4 ؉ /foxp3؉ regulatory T cells (Tregs). The CCR5 ؉ Treg subset exhibited increased IL-10 expression, reflecting potent anti-inflammatory activity. Accentuated inflammation in CCR5 ؊/؊ infarcts was associated with increased matrix metalloproteinase (MMP) expression, reduced TIMP levels, and enhanced MMP-2 and MMP-9 activity, resulting in worse cardiac dilation. These results suggest that CCR5-mediated Treg recruitment may restrain postinfarction inflammation, preventing excessive matrix degradation and attenuating adverse remodeling.

The role of transforming growth factor (TGF)-β in the infarcted myocardium

“…Platelets have been suggested to be an important source of TGF-β1 in the pressureoverloaded myocardium (29); however, their role as a source of growth factors in the infarcted myocardium has not been systematically investigated. Lymphocyte subsets and mast cells infiltrate the infarcted heart (30)(31)(32)(33) and are capable of producing TGF-βs. Moreover, much like most tissues, the normal myocardium may contain constitutive stores of matrix-bound latent TGF-β that can be activated following injury (34), initiating a response even in the absence of de novo synthesis.…”

Regulatory T Lymphocytes Attenuate Myocardial Infarction-Induced Ventricular Remodeling in Mice

“…This suggests that chemokine signaling through CCR5 prevents uncontrolled inflammation in the infarcted myocardium, attenuating matrix degradation and adverse cardiac remodeling. 24) In conclusion, we proved that adoptive Treg transfer could attenuate cardiac dysfunction after MI via preventing expansion of inflammation and fibrosis. Further studies should be conducted to explore the clinical utility of Treg for the prevention of chronic adverse LV remodeling after MI.…”

HIV Toxins: Gp120 as an Independent Modulator of Cell Function

“…Expression of CCR5 in T CD4 + cells is particularly high in mucosa-associated lymphoid tissues (MALT), where the fraction of CCR5 + CD4+ T cells is >50%. It is known that signaling through CCR5 is significantly involved in the induction of an immunological hyporesponsive state that leads to oral tolerance to high doses of antigen (DePaolo et al, 2004) and prevents uncontrolled postinfarction inflammation of myocardium in mice (Dobaczewski et al, 2010). Anti-inflammatory properties of CCR5 + mononuclear cells have been related to the expression of high levels of IL-10 and their ability to recruit CD4 + /foxp3 + regulatory T cells (Tregs) (Dobaczewski et al, 2010).…”

“…It is known that signaling through CCR5 is significantly involved in the induction of an immunological hyporesponsive state that leads to oral tolerance to high doses of antigen (DePaolo et al, 2004) and prevents uncontrolled postinfarction inflammation of myocardium in mice (Dobaczewski et al, 2010). Anti-inflammatory properties of CCR5 + mononuclear cells have been related to the expression of high levels of IL-10 and their ability to recruit CD4 + /foxp3 + regulatory T cells (Tregs) (Dobaczewski et al, 2010). The expression of CXCR4 on the cell surface is increased by several cytokines (IL-4, IL-2, IL-7, IL-10, IL-5, TGF-1), as well as by fibroblast and vascular growth factors, whereas it is reduced by others, mainly those pro-inflammatory cytokines (TNF-alpha, INF-gamma, and IL-1-beta).…”