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Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing
Kristine Y. DeLeon-Pennell, … , Yonggang Ma, Merry L. Lindsey
Kristine Y. DeLeon-Pennell, … , Yonggang Ma, Merry L. Lindsey
Published September 21, 2017
Citation Information: JCI Insight. 2017;2(18):e94207. https://doi.org/10.1172/jci.insight.94207.
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Categories: Research Article Cardiology Inflammation

Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing

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Abstract

Chronic inflammatory diseases, such as periodontal disease, associate with adverse wound healing in response to myocardial infarction (MI). The goal of this study was to elucidate the molecular basis for impaired cardiac wound healing in the setting of periodontal-induced chronic inflammation. Causal network analysis of 168 inflammatory and extracellular matrix genes revealed that chronic inflammation induced by a subseptic dose of Porphyromonas gingivalis lipopolysaccharide (LPS) exacerbated infarct expression of the proinflammatory cytokine Ccl12. Ccl12 prevented initiation of the reparative response by prolonging inflammation and inhibiting fibroblast conversion to myofibroblasts, resulting in diminished scar formation. Macrophage secretion of Ccl12 directly impaired fibronectin and collagen deposition and indirectly stimulated collagen degradation through upregulation of matrix metalloproteinase-2. In post-MI patients, circulating LPS levels strongly associated with the Ccl12 homologue monocyte chemotactic protein 1 (MCP-1). Patients with LPS levels ≥ 1 endotoxin units (EU)/ml (subseptic endotoxemia) at the time of hospitalization had increased end diastolic and systolic dimensions compared with post-MI patients with < 1 EU/ml, indicating that low yet pathological concentrations of circulating LPS adversely impact post-MI left ventricle (LV) remodeling by increasing MCP-1. Our study provides the first evidence to our knowledge that chronic inflammation inhibits reparative fibroblast activation and generates an unfavorable cardiac–healing environment through Ccl12-dependent mechanisms.

Authors

Kristine Y. DeLeon-Pennell, Rugmani Padmanabhan Iyer, Osasere K. Ero, Courtney A. Cates, Elizabeth R. Flynn, Presley L. Cannon, Mira Jung, De’Aries Shannon, Michael R. Garrett, William Buchanan, Michael E. Hall, Yonggang Ma, Merry L. Lindsey

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Figure 6

Macrophage secretion of Ccl12 regulates wound healing by decreasing myofibroblast activation and increasing proliferation.

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Macrophage secretion of Ccl12 regulates wound healing by decreasing myof...
(A) Stimulating naive fibroblasts with macrophage conditioned media isolated from lipopolysaccharide-preexposed MI mice (LPS+MI) increased cell proliferation but had no effect on cell migration. n = 4/group (4M); 4.5 ± 0.1 months for all groups. (B) Fibroblasts stimulated with macrophage conditioned media from LPS+MI mice decreased gene levels of α–smooth muscle actin (αSMA), collagen I, and TGFβ1 and increased BrdU uptake to indicate increased fibroblasts proliferation. n = 6/group (4M); 4.0 ± 0.1 months for all groups. (C) Secretion of extracellular matrix (ECM) decreased in fibroblasts stimulated with macrophage media from LPS+MI mice as shown by decreased procollagen and fibronectin protein. Ccl12 blocking antibody (Ccl12i) attenuated the effect of the LPS+MI macrophage secretome. n = 6/group (6M); 4.0 ± 0.1 months for all groups. All in vitro stimulation experiments were paired. Data is shown as box and whisker plots with mean ± minimum/maximum; one-way ANOVA with Student Newman-Keuls post-test; *P < 0.05 vs. MI; †P < 0.05 vs. LPS+MI.
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