Lipopolysaccharides from atherosclerosis-associated bacteria antagonize TLR4, induce formation of TLR2/1/CD36 complexes in lipid rafts and trigger TLR2-induced inflammatory responses in human vascular endothelial cells

Abstract

SummaryInfection with bacteria such as Chlamydia pneumonia, Helicobacter pylori or Porphyromonas gingivalis may be triggering the secretion of inflammatory cytokines that leads to atherogenesis. The mechanisms by which the innate immune recognition of these pathogens could lead to atherosclerosis remain unclear. In this study, using human vascular endothelial cells or HEK-293 cells engineered to express pattern-recognition receptors (PRRs), we set out to determine Toll-like receptors (TLRs) and functionally associated PRRs involved in the innate recognition of and response to lipopolysaccharide (LPS) from H. pylori or P. gingivalis. Using siRNA interference or recombinant expression of cooperating PRRs, we show that H. pylori and P. gingivalis LPS-induced cell activation is mediated through TLR2. Human vascular endothelial cell activation was found to be lipid raftdependent and to require the formation of heterotypic receptor complexes comprising of TLR2, TLR1, CD36 and CD11b/CD18. In addition, we report that LPS from these bacterial strains are able to antagonize TLR4. This antagonistic activity of H. pylori or P. gingivalis LPS, as well as their TLR2 activation capability may be associated with their ability to contribute to atherosclerosis.

Is Porphyromonas gingivalis Cell Invasion Required for Atherogenesis? Pharmacotherapeutic Implications

“…Therefore, in addition to the invasion deficiency, DPG3 lacks FimA, a known potent TLR2 ligand, and pathogenicity may be reduced to only LPS (36 -38, 40). Our recent investigation corroborated by other laboratories shows that TLR2 Ϫ/Ϫ mice exhibit substantially reduced lesions of P. gingivalis-induced atherosclerosis compared with TLR2 ϩ/ϩ and TLR2 ϩ/Ϫ mice, and mice injected with FSL-1, a TLR2 agonist, also showed a similar increase in atherosclerotic lesion size, irrespective of the diet (4,(42)(43)(44). The reduction of atherosclerosis observed when animals were infected with DPG3 may not be the result of only lack of invasion capability, but also lack of cell surface-initiated signaling by the FimA.…”

Identification of Signaling Pathways in Macrophage Exposed to Porphyromonas gingivalis or to Its Purified Cell Wall Components

“…The study by Triantafilou et al (28) showed that the silencing of TLR7 did not affect the production of TNF-␣ in human vascular endothelial cells in response to P. gingivalis LPS. However, in our study we used macrophages, a cell type that is different from endothelial cells, which can explain the discrepancy.…”

“…Another widely studied surface structure of P. gingivalis is its LPS, which displays significant structural and biological differences from the LPS of E. coli (34). Both P. gingivalis and its purified cell surface components (LPS and FimA) are detected predominantly by TLR2 of the innate immune system resulting in host cell activation (9,28,35), although activation of TLR4 by P. gingivalis LPS has also been reported (14). Our previous studies demonstrated that macrophages respond differently to live P. gingivalis, when compared with its LPS or its FimA, in the context of cytokine secretion and intracellular molecule induction (7,9,10).…”

Perioperative Management of Carcinoid Syndorme-An Anaesthesiologist’s Perspective

“…Somatostatin & its analog octreotide is the primary drug that is used in preparation. It inhibits the exocrine and endocrine secretions from gut thereby controlling signs and symptoms of Carcinoid tumor and preventing Carcinoid crisis [14,15]. The half-life of somatostatin is 1 to 3 min, and that of octreotide is 1.5 to 3 hrs.…”