Unique lipids from a common human bacterium represent a new class of Toll-like receptor 2 ligands capable of enhancing autoimmunity.
Recent reports suggest that commensal bacteria may play a down-regulatory role in autoimmune disease. In the present studies, we demonstrate that phosphorylated dihydroceramides, uniquely structured lipids derived from the common human oral bacterium Porphyromonas gingivalis and from bacteria commonly found in the gastrointestinal tract and other organs, are capable of enhancing autoimmunity. We have previously reported that these lipids have proinflammatory effects on human fibroblasts in vitro and, in preliminary studies, have recovered these lipids from surgically removed human carotid atheroma, suggesting that they may play a role in human inflammatory disease. To investigate whether these lipids have functional effects on autoimmunity, we administered phosphorylated dihydroceramides to mice with the murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). We find that these lipids, and particularly the phosphoethanolamine dihydroceramide (PE DHC) fraction, significantly enhanced EAE. Mechanistically, PE DHC enhances EAE in mice lacking natural killer T cells, fails to enhance EAE in Toll-like receptor 2 (TLR2)-deficient mice and, in vitro, induces dendritic cell interleukin-6 secretion in a TLR2-dependent manner. Finally, PE DHC-treated mice with EAE demonstrate a decreased percentage of spinal cord Foxp3+ T cells, suggesting that these lipids may affect regulatory aspects of adaptive immune responses. Overall, our results suggest that phosphorylated dihydroceramides derived from common human bacteria function as TLR2 ligands and may play a previously unrecognized role in human autoimmune diseases.
Division of Periodontology, Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
Frank C
FC
Nichols
William J
WJ
Housley
Catherine A
CA
O'Conor
Thomas
T
Manning
Shuang
S
Wu
Robert B
RB
Clark
D000818:Animals; D015551:Autoimmunity; D002518:Ceramides / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016966:Porphyromonas gingivalis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*
D002518:Ceramides; D008024:Ligands; D008055:Lipids; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C109343:dihydroceramide