Complement Receptor 3 Blockade Promotes IL-12-Mediated Clearance of <i>Porphyromonas gingivalis</i> and Negates Its Virulence In Vivo

Hajishengallis, George; Shakhatreh, Muhamad-Ali K.; Wang, Min; Liang, Shuang

doi:10.4049/jimmunol.179.4.2359

Cited by 112 publications

(167 citation statements)

References 64 publications

(76 reference statements)

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“…Consistent with earlier results (Takeshita et al, 1998), we found that mouse or human CR3 contributes to induction of several proinflammatory cytokines by P. gingivalis fimbriae, including TNF-α, IL-1β, and IL-6 Hajishengallis et al, 2006a;Hajishengallis et al, 2007). Strikingly, however, the binding of P. gingivalis fimbriae to activated CR3 results in reduced production of bioactive (p70) IL-12 Hajishengallis et al, 2007), a key cytokine involved in intracellular bacterial clearance (Trinchieri, 2003).…”

Section: P Gingivalis Interaction With Cr3 Downregulates Il-12 Inducsupporting

confidence: 91%

“…Strikingly, however, the binding of P. gingivalis fimbriae to activated CR3 results in reduced production of bioactive (p70) IL-12 Hajishengallis et al, 2007), a key cytokine involved in intracellular bacterial clearance (Trinchieri, 2003). At the mechanistic level, suppression of IL-12p70 production is mediated by CR3-dependent phosphorylation of ERK1/2 which leads to downregulation of IL-12 p35 and p40 subunits (Fig.…”

Section: P Gingivalis Interaction With Cr3 Downregulates Il-12 Inducmentioning

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: P Gingivalis Interaction With Cr3 Downregulates Il-12 Inducsupporting

confidence: 91%

Section: P Gingivalis Interaction With Cr3 Downregulates Il-12 Inducmentioning

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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“…IL-12-deficient mice are defective in IFN-␥ production (48), implying that IFN-␥ could be involved in the clearance of this pathogen (47). In addition, IL-12 attenuated the persistence and virulence of P. gingivalis in experimental mouse periodontitis (49). These findings suggest that IL-10 and IL-12 likely play complex and multifaceted roles in oral vs extraoral infections with P. gingivalis, and that the pathogenic role of IL-12 may be predominantly exerted under conditions of functional IL-10 deficiency.…”

Section: Discussionmentioning

confidence: 99%

T Cell Response Mediated by Myeloid Cell-Derived IL-12 Is Responsible for Porphyromonas gingivalis-Induced Periodontitis in IL-10-Deficient Mice

Sasaki¹,

Suzuki

Kent

et al. 2008

The Journal of Immunology

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Periodontal disease is a chronic inflammatory disease in the oral cavity, which culminates in alveolar bone loss. Porphyromonas gingivalis is a consensus periodontal pathogen that has been implicated in adult forms of periodontitis. We previously demonstrated that IL-10-deficient mice exhibit a hyperinflammatory phenotype and are highly susceptible to P. gingivalis-induced periodontitis, indicating an important anti-inflammatory effect of IL-10 in suppressing bone loss. In this study, we analyzed the pathway(s) by which IL-10 deficiency leads to severe P. gingivalis-induced periodontitis. Because Stat3 is essential in IL-10 signaling, immune cell-specific Stat3-deficient mice were subjected to P. gingivalis infection to identify the key IL-10-responsive cells in preventing periodontitis. Myeloid cell-specific Stat3-deficient mice exhibited increased periodontal bone loss (p < 0.001), whereas T cell- and B cell-specific Stat3 mice were resistant, suggesting that macrophages (MP) and/or polymorphonuclear leukocytes are the key target cells normally suppressed by IL-10. Myeloid cell-specific Stat3-deficient mice exhibited elevated gingival CD40L gene expression in vivo compared with wild-type controls (p < 0.01), and Stat3-deficient MPs exhibited vigorous P. gingivalis-stimulated IL-12 production in vitro and induced elevated Ag-specific T cell proliferation compared with wild-type MPs (p < 0.01). Of importance, both IL-12p40/IL-10 and T cell/IL-10 double-deficient mice were resistant to P. gingivalis-induced periodontitis, demonstrating roles for both IL-12p40 and T cells in pathogenesis in a hyperinflammatory model of disease. These data demonstrate that P. gingivalis-induced periodontitis in IL-10-deficient mice is dependent upon IL-12p40-mediated proinflammatory T cell responses.

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“…Hence, activation of TLR2 is modulated by P. gingivalis to its benefit. Recently identified mechanisms by which TLR2 stimulation results in suppression of a bactericidal response, but not in suppression of inflammation, include cross talk between TLR2 and other receptors, including CXCR4 (8), CR3 (9) and C5aR (7). TLR2 has also been shown, by structural and functional studies, to heterodimerize with either TLR1 or TLR6 (10,11).…”

mentioning

confidence: 99%

A Novel Class of Lipoprotein Lipase-Sensitive Molecules Mediates Toll-Like Receptor 2 Activation by Porphyromonas gingivalis

et al. 2013

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Infection by the chronic periodontitis-associated pathogen Porphyromonas gingivalis activates a Toll-like receptor 2 (TLR2) response that triggers inflammation in the host but also promotes bacterial persistence. Our aim was to define ligands on the surfaces of intact P. gingivalis cells that determine its ability to activate TLR2. Molecules previously reported as TLR2 agonists include lipopolysaccharide (LPS), fimbriae, the lipoprotein PG1828, and phosphoceramides. We demonstrate that these molecules do not comprise the major factors responsible for stimulating TLR2 by whole bacterial cells. First, P. gingivalis mutants devoid of the reported protein agonists, PG1828 and fimbriae, activate TLR2 as strongly as the wild type. Second, two-phase extraction of whole bacteria resulted in a preponderance of TLR2 agonist activity partitioning to the hydrophilic phase, demonstrating that phosphoceramides are not a major TLR2 ligand. Third, analysis of LPS revealed that TLR2 activation is independent of lipid A structural variants. Instead, activation of TLR2 and TLR2/TLR1 by LPS is in large part due to copurifying molecules that are sensitive to the action of the enzyme lipoprotein lipase. Strikingly, intact P. gingivalis bacterial cells treated with lipoprotein lipase were attenuated in their ability to activate TLR2. We propose that a novel class of molecules comprised by lipoproteins constitutes the major determinants that confer to P. gingivalis the ability to stimulate TLR2 signaling. Porphyromonas gingivalis is a Gram-negative anaerobic bacterium associated with chronic periodontitis, an inflammatory disease that results in tooth loss (1). P. gingivalis is typically found in diseased subgingival sites (2). Mouse models of P. gingivalis infection have demonstrated its capacity to elicit periodontitis, as measured by bone loss (3-5). A recent study revealed a key role played by P. gingivalis infection in altering the composition, and increasing the abundance, of oral commensal bacteria in conventionally grown mice (4). The interaction between an increasing bacterial load and the host innate immune system triggers a proinflammatory response, which is considered a major factor in causing periodontitis.The Toll-like receptor (TLR) family of innate immune receptors plays a pivotal role in host surveillance and in initiating an immediate immune response that is designed to neutralize microbial threats to the host (6). P. gingivalis infection triggers activation of TLR2, which leads to production of proinflammatory cytokines. One impact of these cytokines is a damaging effect on alveolar bone, resulting in bone loss, as demonstrated by studies using TLR2 Ϫ/Ϫ mice (3, 7). Paradoxically, the robust TLR2 proinflammatory response does not clear P. gingivalis infection in wild-type mice. Instead, the infection is cleared more efficiently in TLR2 Ϫ/Ϫ mice and by macrophages from TLR2 Ϫ/Ϫ mice (3, 5, 7), indicating that TLR2 stimulation confers enhanced persistence to this chronic pathogen. A lack of bacterial clearance illustra...

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Complement Receptor 3 Blockade Promotes IL-12-Mediated Clearance of Porphyromonas gingivalis and Negates Its Virulence In Vivo

Cited by 112 publications

References 64 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

T Cell Response Mediated by Myeloid Cell-Derived IL-12 Is Responsible for Porphyromonas gingivalis-Induced Periodontitis in IL-10-Deficient Mice

A Novel Class of Lipoprotein Lipase-Sensitive Molecules Mediates Toll-Like Receptor 2 Activation by Porphyromonas gingivalis

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