TY - JOUR
T1 - CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells
AU - Dobaczewski, Marcin
AU - Xia, Ying
AU - Bujak, Marcin
AU - Gonzalez-Quesada, Carlos
AU - Frangogiannis, Nikolaos G.
N1 - Funding Information:
Supported by NIH grants R01 HL-76246 and R01 HL-85440 , the Alkek endowment, and the Medallion Foundation.
PY - 2010/5
Y1 - 2010/5
N2 - 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)-1α and MIP-1β 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.
AB - 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)-1α and MIP-1β 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.
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U2 - 10.2353/ajpath.2010.090759
DO - 10.2353/ajpath.2010.090759
M3 - Article
C2 - 20382703
AN - SCOPUS:77952065445
SN - 0002-9440
VL - 176
SP - 2177
EP - 2187
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -