A novel phosphoglycerol serine-glycine lipodipeptide of Porphyromonas gingivalis is a TLR2 ligand

Abstract

Porphyromonas gingivalis is a Gram-negative anaerobic periodontal microorganism strongly associated with tissue destructive processes in human periodontitis. Following oral infection with P. gingivalis, the periodontal bone loss in mice is reported to require engagement of Toll-like receptor 2 (TLR2). Serine-glycine lipodipeptide or glycine aminolipid classes of P. gingivalis engage human and mouse TLR2 but a novel lipid class reported here is considerably more potent in engaging TLR2 and the heterodimer receptor TLR2/TLR6. The novel lipid class, termed Lipid 1256, consists of a diacylated phosphoglycerol moiety linked to a serine-glycine lipodipeptide, previously termed Lipid 654. Lipid 1256 is approximately 50-fold more potent in engaging TLR2 than the previously reported serine-glycine lipid classes. Lipid 1256 also stimulates cytokine secretory responses from peripheral blood monocytes and is recovered in selected oral and intestinal Bacteroidetes organisms. Therefore, these findings suggest that Lipid 1256 may be a microbial TLR2 ligand relevant to chronic periodontitis in humans.

Serine/Glycine Lipid Recovery in Lipid Extracts From Healthy and Diseased Dental Samples: Relationship to Chronic Periodontitis

“…Lipid 1256 isolated from P. gingivalis was recently reported to significantly promote monocyte release of TNF-α and IL-1β from freshly isolated human peripheral blood monocytes [4]. This lipid was also shown to engage human TLR2/TLR6 in transfected human embryonic kidney cells [4]. Bone loss in experimental animals orally gavaged with P. gingivalis is reported to be mediated through engagement of TLR2 [7][8][9].…”

“…The samples were centrifuged and transferred to autosampler tubes. Analysis of lipids utilized mass spectrometric instrumentation located in the Center for Environmental Sciences and Engineering at the University of Connecticut, Storrs as previously described [4]. Routine analysis of lipid samples used a Waters Acquity TM UPLC R coupled with an Acquity TM TQD TM tandem mass spectrometer (Waters Co., Milford, MA).…”

“…Because this unique bacterial fatty acid is recovered essentially only in complex lipids and LPS of bacteria of the Bacteroidetes phylum [1][2][3][4][5], the preferential accumulation of complex lipids containing 3-OH iso C 17 : 0 in subgingival plaque of periodonitis sites suggested a lipid dysbiosis and led to the characterization of lipid classes of P. gingivalis that contain this unique branched fatty acid. The first lipids to be characterized were the phosphorylated dihydroceramides [6] but more recently, serine/glycine lipids of P. gingivalis were characterized because these lipids were observed to engage the innate immune receptor, Toll-like receptor 2 (TLR2) [2][3][4]. It should be emphasized that P. gingivalis is reported to mediate bone loss in experimental animals through engagement of TLR2 [7][8][9].…”

“…Importantly, each lipid class is comprised of at least three species due to subsitution of branched or straight chain fatty acids of differing lengths, but the dominant lipid species in each class are shown in Figure 1 . The most recently characterized serine lipid class, called Lipid 1256 [ 4 ], is the primary focus of this study. As shown in Figure 1 , this lipid is composed of Lipid 654 supplemented with a diacylated phosphoglycerol held in phosphoester linkage to the serine of Lipid 654.…”

Polarized Macrophages in Periodontitis: Characteristics, Function, and Molecular Signaling

“…Their findings also suggested that TLR2 has a microbial stimulation effect and that the activation of macrophages plays a nonnegligible role in this process. Recent cytological studies ( 49 , 50 ) have shown that P.g. is dependent on TLR2 and TLR4 for promoting the secretion of TNF-α in macrophages and is primarily stimulated by glycine lipids, such as serine-glycine dipeptide lipids, of the monomonas factor.…”