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Lipoxin A(4) inhibits porphyromonas gingivalis-induced aggregation and reactive oxygen species production by modulating neutrophil-platelet interaction and CD11b expression
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
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2011 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 4, p. 1489-1497Article in journal (Refereed) Published
Abstract [en]

Porphyromonas gingivalis is an etiological agent that is strongly associated with periodontal disease, and it correlates with numerous inflammatory disorders, such as cardiovascular disease. Circulating bacteria may contribute to atherogenesis by promoting CD11b/CD18-mediated interactions between neutrophils and platelets, causing reactive oxygen species (ROS) production and aggregation. Lipoxin A(4) (LXA(4)) is an endogenous anti-inflammatory and proresolving mediator that is protective of inflammatory disorders. The aim of this study was to investigate the effect of LXA(4) on the P. gingivalis-induced activation of neutrophils and platelets and the possible involvement of Rho GTPases and CD11b/CD18 integrins. Platelet/leukocyte aggregation and ROS production was examined by lumiaggregometry and fluorescence microscopy. Integrin activity was studied by flow cytometry, detecting the surface expression of CD11b/CD18 as well as the exposure of the high-affinity integrin epitope, whereas the activation of Rac2/Cdc42 was examined using a glutathione S-transferase pulldown assay. The study shows that P. gingivalis activates Rac2 and Cdc42 and upregulates CD11b/CD18 and its high-affinity epitope on neutrophils, and that these effects are diminished by LXA(4). Furthermore, we found that LXA(4) significantly inhibits P. gingivalis-induced aggregation and ROS generation in whole blood. However, in platelet-depleted blood and in isolated neutrophils and platelets, LXA(4) was unable to inhibit either aggregation or ROS production, respectively. In conclusion, this study suggests that LXA(4) antagonizes P. gingivalis-induced cell activation in a manner that is dependent on leukocyte-platelet interaction, likely via the inhibition of Rho GTPase signaling and the downregulation of CD11b/CD18. These findings may contribute to new strategies in the prevention and treatment of periodontitis-induced inflammatory disorders, such as atherosclerosis.

Place, publisher, year, edition, pages
American Society for Microbiology , 2011. Vol. 79, no 4, p. 1489-1497
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-17096DOI: 10.1128/IAI.00777-10ISI: 000288532300010PubMedID: 21263017Scopus ID: 2-s2.0-79953296864OAI: oai:DiVA.org:oru-17096DiVA, id: diva2:438860
Available from: 2011-09-05 Created: 2011-09-02 Last updated: 2019-03-26Bibliographically approved
In thesis
1. The role of peridontitis and hepatocyte growth factor in systemic inflammation
Open this publication in new window or tab >>The role of peridontitis and hepatocyte growth factor in systemic inflammation
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An essential goal in addressing inflammation is the return of tissue to homeostasis. Persistent infections often cause prolonged response and accumulation of immune cells, inducing imbalance in pro- and anti-inflammatory mediators, tissue destruction, and chronic inflammation. In periodontal disease, bacteria of the dental plaque are the primary aetiologic agents. Coronary artery disease (CAD) and chronic renal failure (CRF) are associated with periodontitis and involve systemic inflammation with atherosclerotic and fibrotic processes. The aims of this thesis were to study the effect of the bacterium Porphyromonas gingivalis and the anti-inflammatory mediator lipoxin A4 (LXA4) on blood cells in vitro, as well as to measure the expression of hepatocyte growth factor (HGF) in patients with periodontitis, CAD, and CRF. We found that LXA4 inhibits P. gingivalis–induced leukocyte platelet aggregation and reactive oxygen species (ROS) production in whole blood, by antagonizing the upregulation of CD11b/CD18 on leukocytes. The serum concentration of HGF was elevated in patients with periodontitis, CAD and CRF, indicating a systemic inflammation. However, the biological activity of HGF was reduced in serum from CRF patients and in saliva and gingival crevicular fluid of patients with periodontitis. This finding correlated with reduced growth of gingival epithelial cells incubated with saliva from patients with periodontitis. Neutrophil proteases reduced the biological activity of HGF in patients with CRF, and HGF expression in patients with periodontitis was associated with higher concentration and numbers of species of periodontal bacteria. In conclusion, these studies suggest that systemic spreading of periodontal bacteria, leukocyte-platelet activation and disturbed HGF-expression are crucial components involved in tissue degradation and progression of chronic inflammation.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013. p. 86
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 83
Keywords
Hepatocyte growth factor, Porphyromonas gingivalis, periodontitis, systemic inflammation, coronary artery disease, chronic renal failure, lipoxin
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-28541 (URN)978-91-7668-922-6 (ISBN)
Public defence
2013-05-08, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2017-10-17Bibliographically approved

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Lönn, JohannaRamström, SofiaSärndahl, EvaBengtsson, Torbjörn

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