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Anticardiolipin (aCL) in sera from periodontitis subjects activate Toll-like receptor 4 (TLR4).

ABSTRACT: Anticardiolipin antibodies (aCL) have been reported to be present in 15-20% of sera from subjects with periodontitis at concentrations exceeding those found in 95% of the healthy adult population. These antibodies, albeit at concentrations exceeding those generally found in periodontitis subjects, are typically present in patients with the antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. aCL from APS patients are proinflammatory and can activate trophoblasts, macrophages, and platelets via cell-surface interactions with their target antigen beta-2-glycoprotein-I (?2GPI). ?2GPI is an anionic phospholipid-binding serum protein that can associate with toll-like receptors (TLR's) on the cell-surface, leading to cell activation following interaction with autoimmune aCL. We examined an expanded series of 629 sera from clinically characterized subjects for aCL content, and observed that 14-19% of these sera contained elevated (>95th %-tile) levels of aCL. We purified IgG from 16 subjects with elevated or normal levels of aCL and examined their ability to activate TLR2- or TLR4-transfected human embryonic kidney (HEK) cells, and observed that IgG from periodontitis patients with elevated aCL activated HEK-TLR4 cells, but not HEK-TLR2 cells. Prior removal of aCL by immunoabsorption significantly reduced the ability of IgG preparations from these sera to activate TLR4. Further experiments using a human first trimester trophoblastic cell line (HTR8 sv/neo) revealed that aCL from periodontitis patients stimulated IL-8 production, which was profoundly decreased if aCL was removed by immunoabsorption or if HTR8 sv/neo were pretreated with blocking anti-TLR4 antibodies. Thus, it appears that aCL from periodontitis patients can be proinflammatory, activating cells via TLR4. Since these antibodies are likely produced via molecular mimicry due to similarities between oral bacterial antigens and ?2GPI, the data indicate that circulating serum aCL may induce or influence inflammatory responses at sites distant from the oral cavity.

SUBMITTER: Schenkein HA

PROVIDER: S-EPMC6128564 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Anticardiolipin (aCL) in sera from periodontitis subjects activate Toll-like receptor 4 (TLR4).

Schenkein Harvey A HA Thomas Ravindar R RR

PloS one 20180907 9

Anticardiolipin antibodies (aCL) have been reported to be present in 15-20% of sera from subjects with periodontitis at concentrations exceeding those found in 95% of the healthy adult population. These antibodies, albeit at concentrations exceeding those generally found in periodontitis subjects, are typically present in patients with the antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. aCL from APS patients are proinflammatory and ...[more]

PMID: 30192824

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Project description:Macrophages are important immune sentinels that detect and clear pathogens and initiate inflammatory responses through the activation of surface receptors, including Toll-like receptors (TLRs). Activated TLRs employ complex cellular trafficking and signalling pathways to initiate transcription for inflammatory cytokine programs. We have previously shown that Rab8a is activated by multiple TLRs and regulates downstream Akt/mTOR signalling by recruiting the effector PI3Kγ, but the guanine nucleotide exchange factors (GEF) canonically required for Rab8a activation in TLR pathways is not known. Using GST affinity pull-downs and mass spectrometry analysis, we identified a Rab8 specific GEF, GRAB, as a Rab8a binding partner in LPS-activated macrophages. Co-immunoprecipitation and fluorescence microscopy showed that both GRAB and a structurally similar GEF, Rabin8, undergo LPS-inducible binding to Rab8a and are localised on cell surface ruffles and macropinosomes where they coincide with sites of Rab8a mediated signalling. Rab nucleotide activation assays with CRISPR-Cas9 mediated knock-out (KO) cell lines of GRAB, Rabin8 and double KOs showed that both GEFs contribute to TLR4 induced Rab8a GTP loading, but not membrane recruitment. In addition, measurement of signalling profiles and live cell imaging with the double KOs revealed that either GEF is individually sufficient to mediate PI3Kγ-dependent Akt/mTOR signalling at macropinosomes during TLR4-driven inflammation, suggesting a redundant relationship between these proteins. Thus, both GRAB and Rabin8 are revealed as key positive regulators of Rab8a nucleotide exchange for TLR signalling and inflammatory programs. These GEFs may be useful as potential targets for manipulating inflammation. Abbreviations: TLR: Toll-like Receptor; OCRL: oculocerebrorenal syndrome of Lowe protein; PI3Kγ: phosphoinositol-3-kinase gamma; LPS: lipopolysaccharide; GEF: guanine nucleotide exchange factor; GST: glutathione S-transferases; BMMs: bone marrow derived macrophages; PH: pleckstrin homology; GAP: GTPase activating protein; ABCA1: ATP binding cassette subfamily A member 1; GDI: GDP dissociation inhibitor; LRP1: low density lipoprotein receptor-related protein 1.

Dataset Information

Anticardiolipin (aCL) in sera from periodontitis subjects activate Toll-like receptor 4 (TLR4).

Publications

Anticardiolipin (aCL) in sera from periodontitis subjects activate Toll-like receptor 4 (TLR4).

Similar Datasets

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