Lipoxin A ₄ Inhibits Porphyromonas gingivalis -Induced Aggregation and Reactive Oxygen Species Production by Modulating Neutrophil-Platelet Interaction and CD11b Expression

Abstract

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.Periodontitis is one of the most prevalent inflammatory diseases in humans, the key etiologic agent being the Gramnegative anaerobic rod Porphyromonas gingivalis (54). This bacterium not only is involved in tooth loss but also may cause recurrent bacteremias and contribute to systemic disorders, such as cardiovascular disease (10,22,23,39,46,65). P. gingivalis expresses a broad range of virulence factors, such as cysteine proteinases (gingipains), fimbriae, lipopolysaccharide (LPS), and capsular polysaccharide. Infection with the bacterium may lead to chronic inflammation in which hyperresponsive neutrophils contribute to host-mediated tissue destruction. P. gingivalis has been found in human atherosclerotic plaques (15,27) and has been shown to promote the phenotypic switch of murine monocytes into foam cells, e.g., by inducing reactive oxygen species (ROS) generation and the oxidation of lowdensity lipoprotein (LDL) (31,38,57).We have recently reported that the exposure of human blood to P. gingivalis causes the formation of atherogenic LDL through a gingipain-mediated cleavage of apoB-100...

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