CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells

Marcin Dobaczewski, Ying Xia, Marcin Bujak, Carlos Gonzalez-Quesada, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

155 Citations (Scopus)

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)-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.

Original languageEnglish (US)
Pages (from-to)2177-2187
Number of pages11
JournalAmerican Journal of Pathology
Volume176
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

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CCR5 Receptors
Regulatory T-Lymphocytes
Inflammation
Interleukin-10
Macrophage Inflammatory Proteins
Chemokines
Anti-Inflammatory Agents
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Matrix Metalloproteinases
Dilatation
Myocardium
Leukocytes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells. / Dobaczewski, Marcin; Xia, Ying; Bujak, Marcin; Gonzalez-Quesada, Carlos; Frangogiannis, Nikolaos G.

In: American Journal of Pathology, Vol. 176, No. 5, 05.2010, p. 2177-2187.

Research output: Contribution to journalArticle

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