Lipoxin A₄ inhibits porphyromonas gingivalis-induced aggregation and reactive oxygen species production by modulating neutrophil-platelet interaction and CD11b expression.
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 A₄ (LXA₄) 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 LXA₄ 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 LXA₄. Furthermore, we found that LXA₄ significantly inhibits P. gingivalis-induced aggregation and ROS generation in whole blood. However, in platelet-depleted blood and in isolated neutrophils and platelets, LXA₄ was unable to inhibit either aggregation or ROS production, respectively. In conclusion, this study suggests that LXA₄ 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.
Division of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden. johanna.lonn@oru.se
Emma
E
Börgeson
Johanna
J
Lönn
Ida
I
Bergström
Veronika Patcha
VP
Brodin
Sofia
S
Ramström
Fariba
F
Nayeri
Eva
E
Särndahl
Torbjörn
T
Bengtsson
D050197:Atherosclerosis / Q000378:metabolism / Q000382:microbiology; D016866:Bacteroidaceae Infections / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D039481:CD11b Antigen / Q000096:biosynthesis*; D018821:CD18 Antigens / Q000378:metabolism; D002449:Cell Aggregation / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D044045:Lipoxins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016966:Porphyromonas gingivalis / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D039481:CD11b Antigen; D018821:CD18 Antigens; D044045:Lipoxins; D017382:Reactive Oxygen Species; C040527:lipoxin A4; D020741:rho GTP-Binding Proteins
Blood. 1999 Dec 15;94(12):4132-42
10590058
Inflamm Res. 2010 Feb;59(2):89-95
19669698
Infect Immun. 2006 Oct;74(10):5658-66
16988241
J Immunol. 2003 Dec 15;171(12):6856-65
14662892
Scand J Clin Lab Invest. 2002;62(6):451-61
12469900
Am J Cardiol. 2005 Feb 15;95(4):452-6
15695127
J Biol Chem. 1999 May 7;274(19):13198-204
10224076
FEMS Microbiol Immunol. 1990 Dec;2(5-6):285-93
2149986
J Dent Res. 2006 Feb;85(2):106-21
16434728
Periodontol 2000. 2006;40:144-63
16398691
Br J Pharmacol. 2009 Oct;158(4):947-59
19785661
Microb Pathog. 2003 Dec;35(6):259-67
14580389
Eur J Pharmacol. 2006 Apr 24;536(1-2):19-27
16564523
ScientificWorldJournal. 2010 Jul 07;10:1370-85
20623097
J Exp Med. 1994 Jul 1;180(1):253-60
8006586
Circulation. 2004 Jun 8;109(22):2801-6
15123526
Front Biosci. 2007 May 01;12:4547-57
17485396
FASEB J. 2008 Oct;22(10):3595-606
18559988
Am J Pathol. 2002 Jun;160(6):2275-83
12057930
Eur J Pharmacol. 2009 Aug 1;615(1-3):207-17
19445920
Prostaglandins Leukot Essent Fatty Acids. 2005 Sep-Oct;73(3-4):257-62
15979865
J Biol Chem. 1994 Dec 9;269(49):30749-52
7982999
Circulation. 1996 Sep 15;94(6):1239-46
8822975
Haemostasis. 1999 Sep;29(1):41-9
10494033
J Am Coll Cardiol. 1998 Feb;31(2):352-8
9462579
Eur J Immunol. 2005 Apr;35(4):1201-10
15739163
Exp Cell Res. 2004 Nov 1;300(2):308-19
15474996
J Periodontol. 2003 Jan;74(1):85-9
12593601
Am J Pathol. 2004 Mar;164(3):937-46
14982847
J Biomed Mater Res A. 2009 Jun 15;89(4):951-9
18470919
Proc Natl Acad Sci U S A. 1984 Sep;81(17):5335-9
6089195
J Periodontal Res. 2004 Feb;39(1):1-9
14687221
Prostaglandins Leukot Essent Fatty Acids. 2005 Sep-Oct;73(3-4):289-99
15979867
Clin Microbiol Infect. 2007 Oct;13 Suppl 4:3-10
17716290
Thromb Haemost. 2010 Feb;103(2):398-407
20024498
FASEB J. 2006 Feb;20(2):401-3
16373400
J Immunol. 2006 Jun 15;176(12):7645-56
16751412
Ann Periodontol. 1998 Jul;3(1):151-60
9722699
J Intern Med. 2008 May;263(5):558-71
18248365
Biochemistry. 2000 Apr 25;39(16):4761-8
10769133
J Periodontal Res. 2005 Feb;40(1):87-95
15613084
Curr Top Microbiol Immunol. 2005;291:91-111
15981461
J Biol Chem. 2004 Jul 2;279(27):28136-42
15123662
J Periodontol. 2000 Oct;71(10):1554-60
11063387
Oral Microbiol Immunol. 2000 Dec;15(6):393-6
11154438
J Leukoc Biol. 2003 Oct;74(4):611-9
12960248
J Cell Sci. 1997 Apr;110 ( Pt 7):881-7
9133675
J Cell Biol. 1993 Jan;120(2):545-56
7678422
J Biol Chem. 1993 Oct 5;268(28):20983-7
8407934
J Periodontol. 2005 Dec;76(12):2187-93
16332229
Curr Opin Cell Biol. 1997 Oct;9(5):643-50
9330867
Autophagy. 2006 Jul-Sep;2(3):165-70
16874051
PLoS One. 2007 Oct 24;2(10):e1056
17957240
Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1245-9
12763762
Infect Immun. 2006 Jul;74(7):4214-23
16790796
Am J Cardiol. 2004 Feb 15;93(4):410-3
14969612
Infect Immun. 1999 Nov;67(11):5792-8
10531230
Nature. 1994 Jan 6;367(6458):40-6
8107774
Cell Signal. 2008 Mar;20(3):557-68
18164590
Nat Rev Immunol. 2008 May;8(5):349-61
18437155
Thromb Haemost. 1998 Jan;79(1):177-85
9459345
Cell Signal. 1999 Sep;11(9):621-35
10530871
Platelets. 2002 Feb;13(1):21-30
11918833
Circ Res. 2009 Feb 13;104(3):346-54
19106411
Expert Opin Ther Targets. 2004 Dec;8(6):643-52
15584868
Circulation. 2002 Feb 19;105(7):861-7
11854128
J Immunol. 2006 Feb 1;176(3):1878-88
16424219
Free Radic Biol Med. 1999 Feb;26(3-4):431-8
9895235
Cell Microbiol. 2008 May;10(5):1181-9
18182086
Platelets. 2008 Aug;19(5):352-8
18791941