Vesicle-independent extracellular release of a proinflammatory outer membrane lipoprotein in free-soluble form

Karched, Maribasappa; Ihalin, Riikka; Eneslätt, Kjell; Zhong, Dan; Oscarsson, Jan; Wai, Sun Nyunt; Chen, Casey; Asikainen, Sirkka

doi:10.1186/1471-2180-8-18

Cited by 29 publications

(48 citation statements)

References 71 publications

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“…A possible explanation for such observations may be that endocytic pathways differ based on the size of the particle (65,66). Thus, as A. actinomycetemcomitans, similar to many additional bacterial species, disseminates vesicles of heterogenous sizes (approximately 10 to 300 nm in diameter) (3,7,19,48), differentially sized subpopulations of bacterial OMVs may be internalized via discrete pathways of endocytosis. A. actinomycetemcomitans OMV uptake was only partly reduced by filipin III, an inhibitor of caveola-dependent endocytosis (62,67,68), preventing OMV colocalization with caveolin protein (69).…”

Section: Discussionmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles Are Internalized in Human Host Cells and Trigger NOD1- and NOD2-Dependent NF-κB Activation

et al. 2014

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Section: Discussionmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles Are Internalized in Human Host Cells and Trigger NOD1- and NOD2-Dependent NF-κB Activation

et al. 2014

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“…For example, A. actinomycetemcomitans OMVs were demonstrated to be enriched with biologically active leukotoxin (LtxA) (15,32), an RTX toxin (repeats in toxin) that lyses cells of the lymphocytic and monomyelocytic lineages (38,59). Moreover, OmpA and the GroEL homologue of A. actinomycetemcomitans, which can activate several different types of mammalian cells, have been found in OMVs (22,32,55), and so has peptidoglycan-associated lipoprotein (PAL), which exhibits a proinflammatory activity on human whole blood (31).…”

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Perinuclear Localization of Internalized Outer Membrane Vesicles Carrying Active Cytolethal Distending Toxin from Aggregatibacter actinomycetemcomitans

et al. 2012

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Aggregatibacter actinomycetemcomitans is implicated in aggressive forms of periodontitis. Similarly to several other Gramnegative species, this organism produces and excretes a cytolethal distending toxin (CDT), a genotoxin associated with cell distention, G 2 cell cycle arrest, and/or apoptosis in many mammalian cell types. In this study, we have identified A. actinomycetemcomitans outer membrane vesicles (OMVs) as a vehicle for simultaneous delivery of multiple proteins, including CDT, into human cells. The OMV proteins were internalized in both HeLa cells and human gingival fibroblasts (HGF) via a mechanism of OMV fusion with lipid rafts in the plasma membrane. The active toxin unit, CdtB, was localized inside the nucleus of the intoxicated cells, whereas OmpA and proteins detected using an antibody specific to whole A. actinomycetemcomitans serotype a cells had a perinuclear distribution. In accordance with a tight association of CdtB with OMVs, vesicles isolated from A. actinomycetemcomitans strain D7SS (serotype a), in contrast to OMVs from a D7SS cdtABC mutant, induced a cytolethal distending effect on HeLa and HGF cells, indicating that OMV-associated CDT was biologically active. Association of CDT with OMVs was also observed in A. actinomycetemcomitans isolates belonging to serotypes b and c, indicating that OMV-mediated release of CDT may be conserved in A. actinomycetemcomitans. Although the role of A. actinomycetemcomitans OMVs in periodontal disease has not yet been elucidated, our present data suggest that OMVs could deliver biologically active CDT and additional virulence factors into susceptible cells of the periodontium.

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“…Particularly, in the late lesion when the phagocytosis of apoptotic macrophages is impaired, the inflammation and instability of the plaque is increased [45]. We previously demonstrated through an ex- vivo study design that living A. actinomycetemcomitans cells release free-soluble AaPAL [14,27]. Similar to other bacterial lipoproteins [46,47], it can be expected that this small molecule can cross blood vessel barriers while the bacteria remain growing locally.…”

Section: Discussionmentioning

confidence: 99%

“…We found that a 17-kDa AaOMP which was identified as the PAL of A. actinomycetemcomitans (AaPAL) [16] is released by planktonic and biofilm cultures in a soluble form [14,27], which suggests that this molecule can readily disseminate from periodontal pockets into the blood circulation. A significant antibody response to AaPAL in sera of A. actinomycetemcomitans -positive periodontitis patients, but not in the sera of healthy subjects [16], gives evidence of the systemic effect of AaPAL in vivo .…”

Section: Introductionmentioning

confidence: 99%

Peptidoglycan-associated lipoprotein ofAggregatibacter actinomycetemcomitansinduces apoptosis and production of proinflammatory cytokines via TLR2 in murine macrophages RAW 264.7in vitro

Ihalin

Eneslätt

Asikainen

2018

Journal of Oral Microbiology

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Peptidoglycan-associated lipoprotein (PAL) is a conserved pro-inflammatory outer membrane lipoprotein in Gram-negative bacteria. Compared to systemic pathogens, little is known about the virulence properties of PAL in Aggregatibacter actinomycetemcomitans (AaPAL). The aims of this study were to investigate the cytolethality of AaPAL and its ability to induce pro-inflammatory cytokine production in macrophages. Mouse macrophages were stimulated with AaPAL, and the production of IL-1β, IL-6, TNF-α, and MCP-1 was measured after 6, 24, and 48 h. To investigate which receptor AaPAL employs for its interaction with macrophages, anti-toll-like receptor (TLR)2 and anti-TLR4 antibodies were used to block respective TLRs on macrophages. Metabolic activity and apoptosis of the macrophages were investigated after stimulation with AaPAL. AaPAL induced the production of MCP-1, TNF-α, IL-6, and IL-1β from mouse macrophages in order of decreasing abundance. The pre-treatment of macrophages with an anti-TLR2 antibody significantly diminished cytokine production. Under AaPAL stimulation, the metabolic activity of macrophages decreased in a dose- and time-dependent manner. Furthermore, AaPAL induced apoptosis in 56% of macrophages after 48 h of incubation. Our data suggest that AaPAL can kill macrophages by apoptosis. The results also emphasize the role of AaPAL as a potent pro-inflammatory agent in A. actinomycetemcomitans-associated infections.

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Vesicle-independent extracellular release of a proinflammatory outer membrane lipoprotein in free-soluble form

Cited by 29 publications

References 71 publications

Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles Are Internalized in Human Host Cells and Trigger NOD1- and NOD2-Dependent NF-κB Activation

Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles Are Internalized in Human Host Cells and Trigger NOD1- and NOD2-Dependent NF-κB Activation

Perinuclear Localization of Internalized Outer Membrane Vesicles Carrying Active Cytolethal Distending Toxin from Aggregatibacter actinomycetemcomitans

Peptidoglycan-associated lipoprotein ofAggregatibacter actinomycetemcomitansinduces apoptosis and production of proinflammatory cytokines via TLR2 in murine macrophages RAW 264.7in vitro

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