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

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number18
DOIs
StatePublished - Sep 21 2017

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Wound Healing
Lipopolysaccharides
Fibroblasts
Macrophages
Myocardial Infarction
Inflammation
Chemokine CCL2
Endotoxins
Collagen
Porphyromonas gingivalis
Ventricular Remodeling
Endotoxemia
Myofibroblasts
Matrix Metalloproteinase 2
Periodontal Diseases
Fibronectins
Cicatrix
Extracellular Matrix
Hospitalization
Chronic Disease

Keywords

  • Cardiology
  • Cardiovascular disease
  • Chemokines
  • Extracellular matrix
  • Inflammation

Cite this

Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing. / DeLeon-Pennell, Kristine Y.; Iyer, Rugmani Padmanabhan; Ero, Osasere K.; Cates, Courtney A.; Flynn, Elizabeth R.; Cannon, Presley L.; Jung, Mira; Shannon, De'Aries; Garrett, Michael R.; Buchanan, William; Hall, Michael E.; Ma, Yonggang; Lindsey, Merry L.

In: JCI insight, Vol. 2, No. 18, 21.09.2017.

Research output: Contribution to journalArticle

DeLeon-Pennell, KY, Iyer, RP, Ero, OK, Cates, CA, Flynn, ER, Cannon, PL, Jung, M, Shannon, DA, Garrett, MR, Buchanan, W, Hall, ME, Ma, Y & Lindsey, ML 2017, 'Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing', JCI insight, vol. 2, no. 18. https://doi.org/10.1172/jci.insight.94207
DeLeon-Pennell, Kristine Y. ; Iyer, Rugmani Padmanabhan ; Ero, Osasere K. ; Cates, Courtney A. ; Flynn, Elizabeth R. ; Cannon, Presley L. ; Jung, Mira ; Shannon, De'Aries ; Garrett, Michael R. ; Buchanan, William ; Hall, Michael E. ; Ma, Yonggang ; Lindsey, Merry L. / Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing. In: JCI insight. 2017 ; Vol. 2, No. 18.
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AU - Cannon, Presley L.

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AU - Shannon, De'Aries

AU - Garrett, Michael R.

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