Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll‐like receptor 2, and phosphatidylinositol‐3‐kinase

Harokopakis, Evlambia; Hajishengallis, George

doi:10.1002/eji.200425883

Cited by 107 publications

(178 citation statements)

References 39 publications

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“…CR3 exploitation by P. gingivalis is initiated at the level of TLR2, since TLR2 inside-out signaling is required for effective interaction of P. gingivalis fimbriae with CR3 (Harokopakis et al, 2006;Harokopakis and Hajishengallis, 2005). Consistent with this, we have now found that the intracellular survival of fimbriated P. gingivalis is dramatically reduced in TLR2-deficient macrophages relative to normal controls (Fig.…”

Section: Cr3 Exploitation By P Gingivalis Depends On Tlr2supporting

confidence: 80%

“…Rather, CR3 engages in cooperative interactions with the CD14/TLR2 signaling complex in response to P. gingivalis fimbriae. Hajishengallis et al, 2006a;Hajishengallis et al, 2006b;Harokopakis and Hajishengallis, 2005). According to this model, P. gingivalis fimbriae bind CD14 and activate TLR2-and phosphatidylinositol 3-kinase (PI3K)-mediated inside-out signaling leading to activation of the ligand-binding capacity of CR3 (Fig.…”

Section: P Gingivalis Interacts With Crthrough Its Cell Surface Fimbmentioning

confidence: 99%

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Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Hajishengallis

Wang²,

Liang³

et al. 2008

Advances in Experimental Medicine and Biology

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The capacity of certain pathogens to exploit innate immune receptors enables them to undermine immune clearance and persist in their host, often causing disease. Here we review subversive interactions of Porphyromonas gingivalis, a major periodontal pathogen, with the complement receptor-3 (CR3; CD11b/CD18) in monocytes/macrophages. Through its cell surface fimbriae, P. gingivalis stimulates Toll-like receptor-2 (TLR2) inside-out signaling which induces the highaffinity conformation of CR3. Although this activates CR3-dependent monocyte adhesion and transendothelial migration, P. gingivalis has co-opted this TLR2 proadhesive pathway for CR3 binding and intracellular entry. In CR3-deficient macrophages, the internalization of P. gingivalis is reduced 2-fold but its ability to survive intracellularly is reduced 1000-fold, indicating that CR3 is exploited by the pathogen as a relatively safe portal of entry. The interaction of P. gingivalis fimbriae with CR3 additionally inhibits production of bioactive (p70) interleukin-12, which mediates immune clearance. In vivo blockade of CR3 leads to reduced persistence of P. gingivalis in the mouse host and diminished ability to cause periodontal bone loss, the hallmark of periodontal disease. Strikingly, the ability of P. gingivalis to interact with and exploit CR3 depends upon quantitatively minor components (FimCDE) of its fimbrial structure, which predominantly consists of polymerized fimbrillin (FimA). Indeed, isogenic mutants lacking FimCDE but expressing FimA are dramatically less persistent and virulent than the wild-type organism both in vitro and in vivo. This model of immune evasion through CR3 exploitation by P. gingivalis supports the concept that pathogens evolved to manipulate innate immune function for promoting their adaptive fitness.

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Section: Cr3 Exploitation By P Gingivalis Depends On Tlr2supporting

confidence: 80%

Section: P Gingivalis Interacts With Crthrough Its Cell Surface Fimbmentioning

confidence: 99%

Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Hajishengallis

Wang²,

Liang³

et al. 2008

Advances in Experimental Medicine and Biology

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“…It has been shown that TLR2 and CD14 play a crucial role in recognition of FimA by monocytes (6,9). Moreover, membrane-expressed CD14 is an essential coreceptor for TLR2-mediated cell activation by P. gingivalis FimA (6).…”

Section: Resultsmentioning

confidence: 99%

“…Cell culture supernatants were then separated by centrifugation and stored at Ϫ80°C prior to a cytokine protein assay by use of Luminex 100 technology using a multiplex for four cytokines: IL-6, IL-8, GM-CSF, and TNF-␣ (Upstate Cell Signaling Solutions, NY). Human monocytes (1.5 ϫ 10 5 /well) were stimulated as described previously (9). Briefly, monocytes were incubated at 37°C under 5% CO 2 with heat-killed P. gingivalis (MOI, 100:1), Pam3Cys and FSL-1, (both at 1 g/ml), and FimA (1 or 10 g/ml).…”

Section: Methodsmentioning

confidence: 99%

Differential Activation of Human Gingival Epithelial Cells and Monocytes by Porphyromonas gingivalis Fimbriae

2007

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Humans develop periodontitis in response to challenge by microbial dental plaque. Inflammation begins after perturbation of gingival epithelial cells by subgingival bacteria interacting through pattern-recognition receptors, including the Toll-like receptors (TLR). Porphyromonas gingivalis is a major periodontopathogen that interacts with epithelial cells through its cell surface fimbriae (FimA), leading to colonization and/or invasion. Previous work by our group has established membrane CD14 as an essential coreceptor for TLR2-mediated activation of transfected cell lines by P. gingivalis FimA. We have shown that gingival epithelial cells express TLR2 but not CD14 on their cell surfaces. We thus speculated that P. gingivalis FimA does not readily activate epithelial innate immune responses but rather functions to promote P. gingivalis colonization in the absence of a vigorous FimA-induced response. This hypothesis was verified by the findings that primary human gingival epithelial cells responded poorly to FimA in terms of interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha responses, in stark contrast to the marked response to other TLR2 agonists (Pam3Cys, FSL-1) that are not strictly dependent on CD14. On the other hand, CD14-expressing human primary monocytes responded with high levels of the same cytokines to both FimA and the control TLR2 agonists. The gingival epithelial cells failed to respond to FimA even in the presence of exogenously added soluble CD14. These data indicate that the gingival epithelial cell hyporesponsiveness to FimA is attributable to the lack of membrane-expressed but not soluble CD14. In conclusion, P. gingivalis FimA differentially activates human monocytes and epithelial cells, perhaps reflecting different tactics used by P. gingivalis when interacting with different host cell types or a host strategy to limit inflammation.Porphyromonas gingivalis is a gram-negative, black-pigmented bacterium associated with periodontal disease, a condition which results in destruction of the tooth-supporting tissues and loss of teeth (16). P. gingivalis expresses virulence factors involved in host tissue destruction and immune perturbation (10). Adhesion molecules of P. gingivalis include fimbriae (FimA) and hemagglutinins; however, P. gingivalis FimA is considered a critical determinant for the attachment of this microorganism in the oral cavity (16). In this regard, there is strong evidence supporting a crucial role for FimA in P. gingivalis adhesion to several mammalian cells types; indeed, nonfimbriated mutants of P. gingivalis, constructed by inactivation of the FimA gene, display reduced adhesion and invasion of epithelial cells compared to wild-type P. gingivalis (29). Moreover, nonfimbriated mutants display a reduced ability to induce periodontal disease in mice following oral inoculation (19). In this context, P. gingivalis FimA has been shown to induce proinflammatory cytokine release in macrophages (22) as well as inflammatory bon...

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“…In the case of gram-positive bacterial components, evidence suggests that CD14 can enhance TLR2-dependent signaling in macrophages (Harokopakis and Hajishengallis, 2005;Manukyan et al, 2005;Schroder et al, 2003). The majority of Toll-like receptors identified to date utilize a common signal transduction pathway with minor differences that appear to confer specificity in response to distinct ligands (Akira and Hemmi, 2003;Gantner et al, 2003;Takeda et al, 2003).…”

Section: Modulation Of Cd14 Ko Microglial Activation In Response To Bmentioning

confidence: 99%

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

Esen

Kielian

2005

Journal of Neuroimmunology

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Recognition of Staphylococcus aureus and its cell-wall component peptidoglycan (PGN) by microglia is mediated, in part, by Toll-like receptor 2 (TLR2). However, the pattern recognition receptor (PRR) CD14 can also bind PGN and enhance TLR2-mediated signaling in macrophages, suggesting a similar phenomenon might occur in microglia. To assess the functional significance of CD14 on microglial activation, we evaluated the responses of primary microglia isolated from CD14 knockout (KO) and wild type (WT) mice. PGN-dependent microglial activation was partially CD14-dependent as demonstrated by the attenuated expression of TNF-α, macrophage inflammatory protein-2 (MIP-2/CXCL2), and the soluble PRR pentraxin-3 in CD14 KO microglia compared to WT cells. In contrast, microglial responses to intact S. aureus occurred primarily via a CD14-independent manner. Collectively, these findings reveal the complex nature of gram-positive bacterial recognition by microglia, which occurs, in part, via CD14.

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Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll‐like receptor 2, and phosphatidylinositol‐3‐kinase

Cited by 107 publications

References 39 publications

Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Differential Activation of Human Gingival Epithelial Cells and Monocytes by Porphyromonas gingivalis Fimbriae

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

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