PMID- 28931761 OWN - NLM STAT- MEDLINE DCOM- 20190826 LR - 20190826 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 2 IP - 18 DP - 2017 Sep 21 TI - Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing. LID - 94207 [pii] LID - 10.1172/jci.insight.94207 [doi] LID - e94207 AB - 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. FAU - DeLeon-Pennell, Kristine Y AU - DeLeon-Pennell KY AD - Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi, USA. AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Iyer, Rugmani Padmanabhan AU - Iyer RP AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Ero, Osasere K AU - Ero OK AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Cates, Courtney A AU - Cates CA AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Flynn, Elizabeth R AU - Flynn ER AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Cannon, Presley L AU - Cannon PL AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Jung, Mira AU - Jung M AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Shannon, De'Aries AU - Shannon D AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Garrett, Michael R AU - Garrett MR AD - Department of Pharmacology and Toxicology. FAU - Buchanan, William AU - Buchanan W AD - Department of Periodontics and Preventive Science, and. FAU - Hall, Michael E AU - Hall ME AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. AD - Division of Cardiology, University of Mississippi Medical Center, Jackson, Mississippi, USA. FAU - Ma, Yonggang AU - Ma Y AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. FAU - Lindsey, Merry L AU - Lindsey ML AD - Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi, USA. AD - Mississippi Center for Heart Research, Department of Physiology and Biophysics. LA - eng GR - P20 GM103476/GM/NIGMS NIH HHS/United States GR - U54 GM114833/GM/NIGMS NIH HHS/United States GR - P01 HL051971/HL/NHLBI NIH HHS/United States GR - T32 HL105324/HL/NHLBI NIH HHS/United States GR - IK2 BX003922/BX/BLRD VA/United States GR - P20 GM104357/GM/NIGMS NIH HHS/United States GR - R01 HL075360/HL/NHLBI NIH HHS/United States GR - R01 HL129823/HL/NHLBI NIH HHS/United States GR - P30 GM103328/GM/NIGMS NIH HHS/United States GR - U54 GM115428/GM/NIGMS NIH HHS/United States GR - I01 BX000505/BX/BLRD VA/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20170921 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (Ccl12 protein, mouse) RN - 0 (Lipopolysaccharides) RN - 0 (Monocyte Chemoattractant Proteins) MH - Aged MH - Animals MH - Chronic Disease MH - Female MH - Fibroblasts/*metabolism MH - Humans MH - Lipopolysaccharides/administration & dosage MH - Macrophages/*metabolism MH - Male MH - Mice MH - Middle Aged MH - Monocyte Chemoattractant Proteins/*metabolism MH - Myocardium/*metabolism/pathology MH - Periodontitis/chemically induced/*metabolism/pathology MH - Systems Biology MH - *Wound Healing PMC - PMC5621894 OTO - NOTNLM OT - Cardiology OT - Cardiovascular disease OT - Chemokines OT - Extracellular matrix OT - Inflammation COIS- Conflict of interest: The authors have declared that no conflict of interest exists. EDAT- 2017/09/22 06:00 MHDA- 2019/08/27 06:00 PMCR- 2017/09/21 CRDT- 2017/09/22 06:00 PHST- 2017/03/27 00:00 [received] PHST- 2017/08/10 00:00 [accepted] PHST- 2017/09/22 06:00 [pubmed] PHST- 2019/08/27 06:00 [medline] PHST- 2017/09/22 06:00 [entrez] PHST- 2017/09/21 00:00 [pmc-release] AID - 94207 [pii] AID - 10.1172/jci.insight.94207 [doi] PST - epublish SO - JCI Insight. 2017 Sep 21;2(18):e94207. doi: 10.1172/jci.insight.94207. eCollection 2017 Sep 21.