CD36/SR-B2-TLR2 Dependent Pathways Enhance Porphyromonas gingivalis Mediated Atherosclerosis in the Ldlr KO Mouse Model.
There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr°) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls.This increase was entirely CD36/SR-B2-dependent, as there was no significant change in lesion burden between infected and uninfected Cd36o/Ldlro mice [corrected]. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1ß generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release. In the vessel wall, macrophages encountering systemic release of IL1ß, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1ß, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics.
Pediatric Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Paul M
PM
Brown
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America.
David J
DJ
Kennedy
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America.
Richard E
RE
Morton
Department of Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Maria
M
Febbraio
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000097:blood / Q000150:complications* / Q000382:microbiology*; D016866:Bacteroidaceae Infections / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D018955:CD36 Antigens / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005247:Feeding Behavior; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D007371:Interferon-gamma / Q000097:blood; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016966:Porphyromonas gingivalis / Q000187:drug effects / Q000502:physiology*; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism; D012307:Risk Factors; D012850:Sinus of Valsalva / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018955:CD36 Antigens; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011973:Receptors, LDL; D051195:Toll-Like Receptor 2; C099252:oxidized low density lipoprotein; D007371:Interferon-gamma