Porphyromonas gingivalis Mfa1 Induces Chemokine and Cell Adhesion Molecules in Mouse Gingival Fibroblasts via Toll-Like Receptors

Takayanagi, Yuhei; Kikuchi, Takeshi; Hasegawa, Yoshinori; Naiki, Yoshikazu; Goto, Hisashi; Okada, Kousuke; Okabe, Iichiro; Kamiya, Yosuke; Suzuki, Yuki; Sawada, Noritaka; Okabe, Teppei; Kondo, Shun; Ohno, Tasuku; Hayashi, Jun-ichiro; Mitani, Akio

doi:10.3390/jcm9124004

Cited by 8 publications

(9 citation statements)

References 51 publications

(21 reference statements)

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“…These structures participate in auto-aggregation and biofilm formation, and their assembly and structure are similar to the major fimbriae (48). Further, the main subunit, Mfa1, which is not expressed in the W83 strain (43), has been shown to activate fibroblasts in a partially TLR2-dependent manner (26,49). This raises the possibility that not only major fimbriae components, but also minor fimbriae could undergo modification by PPAD which modulates their TLR2-stimulating potential.…”

Section: Discussionmentioning

confidence: 99%

TLR2 Activation by Porphyromonas gingivalis Requires Both PPAD Activity and Fimbriae

et al. 2022

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Porphyromonas gingivalis, a keystone oral pathogen implicated in development and progression of periodontitis, may also contribute to the pathogenicity of diseases such as arthritis, atherosclerosis, and Alzheimer’s. P. gingivalis is a master manipulator of host immune responses due to production of a large variety of virulence factors. Among these, P. gingivalis peptidilarginine deiminase (PPAD), an enzyme unique to P. gingivalis, converts C-terminal Arg residues in bacterium- and host-derived proteins and peptides into citrulline. PPAD contributes to stimulation of proinflammatory responses in host cells and is essential for activation of the prostaglandin E2 (PGE2) synthesis pathway in gingival fibroblasts. Since P. gingivalis is recognized mainly by Toll-like receptor-2 (TLR2), we investigated the effects of PPAD activity on TLR2-dependent host cell responses to P. gingivalis, as well as to outer membrane vesicles (OMVs) and fimbriae produced by this organism. Using reporter cell lines, we found that PPAD activity was required for TLR2 activation by P. gingivalis cells and OMVs. We also found that fimbriae, an established TLR2 ligand, from wild-type ATCC 33277 (but not from its isogenic PPAD mutant) enhanced the proinflammatory responses of host cells. Furthermore, only fimbriae from wild-type ATCC 33277, but not from the PPAD-deficient strains, induced cytokine production and stimulated expression of genes within the PGE2 synthesis pathway in human gingival fibroblasts via activation of the NF-ĸB and MAP kinase-dependent signaling pathways. Analysis of ten clinical isolates revealed that type I FimA is preferable for TLR2 signaling enhancement. In conclusion, the data strongly suggest that both PPAD activity and fimbriae are important for TLR2-dependent cell responses to P. gingivalis infection.

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Section: Discussionmentioning

confidence: 99%

TLR2 Activation by Porphyromonas gingivalis Requires Both PPAD Activity and Fimbriae

et al. 2022

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“…In terms of Mfa1, the recognition receptor remains controversial. We recently reported that TLR4 is mainly important for the recognition of Mfa1 by gingival fibroblasts [ 17 ]. Takahashi et al reported that TLR2 may be important for Mfa1 recognition by bronchial epithelial cells [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, TLR2 is important for P. gingivalis to produce proinflammatory cytokines [ 15 , 16 ]. It has been suggested that TLR2 and TLR4 may be involved in the recognition of P. gingivalis fimbriae [ 17 , 18 ], but a consensus has not been reached so far.…”

Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis Fimbriae Induce Osteoclastogenesis via Toll-like Receptors in RAW264 Cells

Suzuki

Kikuchi

Goto

et al. 2022

IJMS

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The effect of Mfa1 fimbriae of Porphyromonas gingivalis on the progression of bone resorption remains unclear, especially compared with another fimbriae, FimA. We investigated the effect of Mfa1 on osteoclastogenesis together with FimA. We also investigated the role of Toll-like receptors (TLRs) in Mfa1 recognition during osteoclast differentiation. Receptor activator of nuclear factor κβ ligand (RANKL)-prestimulated RAW264 cells were used to examine the effects of purified Mfa1 fimbriae. The number of osteoclasts was examined by tartrate-resistant acid phosphate (TRAP) staining, osteoclast activation was investigated by bone resorption assays, and gene expression of differentiation markers was examined by quantitative real-time PCR. Transfection of Tlr2 and Tlr4 siRNAs into RAW264 cells was also employed and their role in Mfa1 recognition was investigated. Mfa1 effectively induced the formation of TRAP-positive multinucleated cells and activated osteoclasts. Mfa1 also increased gene expression of Acp5, Mmp9, and Ctsk in RANKL-prestimulated RAW264 cells compared with the control. The osteoclastogenesis induced by Mfa1 was significantly decreased in cells transfected with Tlr2 or Tlr4 siRNAs compared with control siRNA. Our results revealed the role of Mfa1 fimbriae in osteoclastogenesis that may contribute to the partial elucidation of the mechanisms of periodontal disease progression and the development of new therapeutic strategies.

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“…Hamada et al reported that purified Mfa1 fimbriae upregulated proinflammatory cytokines, such as IL-1α, IL-β, IL-6, and TNFα, via the TLR2 and CD14 pathways in human monocytes and murine peritoneal macrophages [ 45 , 121 ]. A recent study indicated that recognition by TLR2 and TLR4 was involved in the immunomodulatory actions of purified Mfa1 fimbriae and contributes to the overall action of gingival fibroblasts [ 122 ].…”

Section: Functions Of Fima and Mfa1 Fimbriaementioning

confidence: 99%

“…Therefore, the latter phenotype may not be a direct consequence of accessory protein loss. Our research group recently compared immunomodulation induction by Mfa1 fimbriae purified from the wild type and the mfa5 -deficient mutant lacking the Mfa3–5 tip structure [ 122 ]. The mfa5 mutant presented with relatively upregulated immunomodulatory genes.…”

Section: Functions Of Fima and Mfa1 Fimbriaementioning

confidence: 99%

Porphyromonas gingivalis FimA and Mfa1 fimbriae: Current insights on localization, function, biogenesis, and genotype

Hasegawa

Nagano

2021

Japanese Dental Science Review

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In general, the periodontal pathogen Porphyromonas gingivalis expresses distinct FimA and Mfa1 fimbriae. Each of these consists of five FimA–E and five Mfa1–5 proteins encoded by the fim and mfa gene clusters, respectively. The main shaft portion comprises FimA and Mfa1, whereas FimB and Mfa2 are localized on the basal portion and function as anchors and elongation terminators. FimC–E and Mfa3–5 participate in the assembly of an accessory protein complex on the tips of each fimbria. Hence, they serve as ligands for the receptors on host cells and other oral bacterial species. The crystal structures of FimA and Mfa1 fimbrial proteins were recently elucidated and new insights into the localization, function, and biogenesis of these proteins have been reported. Several studies indicated a correlation between P. gingivalis pathogenicity and the fimA genotype but not the mfa1 genotype. We recently revealed polymorphisms of all genes in the fim and mfa gene clusters. Intriguingly, mfa5 occurred in numerous different forms and underwent duplication. Detailed structural and functional knowledge of the fimbrial proteins in the context of the entire filament could facilitate the development of innovative therapeutic strategies for structure-based drug design.

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Porphyromonas gingivalis Mfa1 Induces Chemokine and Cell Adhesion Molecules in Mouse Gingival Fibroblasts via Toll-Like Receptors

Cited by 8 publications

References 51 publications

TLR2 Activation by Porphyromonas gingivalis Requires Both PPAD Activity and Fimbriae

TLR2 Activation by Porphyromonas gingivalis Requires Both PPAD Activity and Fimbriae

Porphyromonas gingivalis Fimbriae Induce Osteoclastogenesis via Toll-like Receptors in RAW264 Cells

Porphyromonas gingivalis FimA and Mfa1 fimbriae: Current insights on localization, function, biogenesis, and genotype

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