The involvement of C5a in the progression of experimental arthritis with Porphyromonas gingivalis infection in SKG mice

Munenaga, Syuichi; Ouhara, Kazuhisa; Hamamoto, Yuta; Kajiya, Mikihito; Takeda, Katsuhiro; Yamasaki, Satoshi; Kawai, Toshihisa; Mizuno, Noriyoshi; Fujita, Tsuyoshi; Sugiyama, Eiji; Kurihara, Hidemi

doi:10.1186/s13075-018-1744-3

Cited by 26 publications

(36 citation statements)

References 53 publications

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“…All animal experimental procedures employed in this study were approved by the Ethical Committee of Hiroshima University (approved No. A16-33) and performed as previously reported [16]. Briefly, SKG mice were maintained under SPF condition until inoculation of bacteria and feces.…”

Section: Generation Of Pg-infected Experimental Arthritis Mouse Modelmentioning

confidence: 99%

“…We previously showed that systemic or oral Pg administration exacerbated RA-like experimental arthritis in a mouse model [15,16]. Specifically, with systemic Pg infection, bacterial proteins were detected in swelling joint tissues [15].…”

Section: Introductionmentioning

confidence: 99%

“…However, these proteins were not recovered from the Pg oral administration model, likely because the pathogenic effect of Pg in arthritis progression is not through direct bacterial stimulation. Therefore, C5a was suggested as the indirect pathogenic factor, in which increased C5a in periodontal tissues and systemic sites activated osteoclastogenesis in joint tissues [16]. C5a is the complement cleaved from C5 by C5-convertase.…”

Section: Introductionmentioning

confidence: 99%

“…In vivo study using SKG mouse model, the serum in Pg-infected experimental arthritis mouse also showed the increase of C5a level compared to serum in normal experimental arthritis mouse. Furthermore, C5a in serum from strongly induced osteoclasrgenesis Pginfected experimental arthritis mouse [16]. Therefore, C5a induced by Pg infection were focused on as tone of the factor for arthritis exacerbation.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies showed the involvement of Pg in the exacerbation of experimental arthritis [15]. The mechanisms of Pg-induced arthritis included the variant immune response in T cells, activation of osteoclastogenesis in joint tissues, systemic and local C5a elevation, and change in gut microbiota [16]. In humans, serum ACPA is used as a marker for RA diagnosis.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Porphyromonas gingivalis infection on gut dysbiosis and arthritis exacerbation in mouse model

Hamamoto

Ouhara

Munenaga³

et al. 2020

Preprint

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Background: Porphyromonas gingivalis (Pg) infection causes periodontal disease and is involved in the exacerbation of rheumatoid arthritis (RA). Gut microbiota dysbiosis has shown strong associations with systemic diseases, including RA, diabetes mellitus, and inflammatory bowel disease, and inoculation of periodontopathogenic bacteria (i.e. Pg) can alter gut microbiota composition. Therefore, this study investigated dysbiosis-mediated arthritis exacerbation by Pg oral inoculation in an experimental arthritis model mouse.Methods: Pg inoculation in the oral cavity twice a week for 6 weeks was performed to induce periodontitis in SKG mice. Concomitantly, a single intraperitoneal (i.p.) injection of laminarin (LA) was administered to induce experimental arthritis (Pg-LA mouse). Citrullinated protein (CP) and IL-6 levels in periodontal, intestinal, and joint tissues, and serum were measured by ELISA. Gut microbiota composition was determined by sequencing the bacterial 16S rRNA after DNA purification of mouse feces. Fecal microbiota transplantation (FMT) was performed by transferring Pg-RA-derived feces to normal SKG mice. The effect of the Pg peptidylarginine deaminase (PgPAD) on the level of citrullinated proteins and arthritis progression were determined using PgPAD knockout mutant.Results: Periodontal alveolar bone loss and IL-6 in gingival tissue were induced by Pg oral infection, as well as severe joint destruction, increased arthritis scores (AS), and IL-6 and CP production in serum, joint, and intestinal tissues. Distribution of Deferribacteres and S24-7 was decreased, while CP was significantly increased in gingival, joint, and intestinal tissues of Pg-inoculated experimental arthritis mice compared to experimental arthritis mice without Pg inoculation. Further, FMT from Pg-inoculated experimental arthritis mice showed the reproduction of donor gut microbiota and resulted in severe joint destruction with increased IL-6 and CP production in joint and intestinal tissues. The avarage AS of FMT from Pg-inoculated experimental arthritis was much higher than that of donor mouse. However, inoculation of the PgPAD knockout mutant inhibited the elevation of arthritis scores, ACPA level in serum and reduced CP amount in gingival, joint, and intestinal tissues compared to Pg wild type inoculation .Conclusion: Pg oral infection affected gut microbiota dysbiosis and joint destruction via increased CP generation.

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Section: Generation Of Pg-infected Experimental Arthritis Mouse Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Effect of Porphyromonas gingivalis infection on gut dysbiosis and arthritis exacerbation in mouse model

Hamamoto

Ouhara

Munenaga³

et al. 2020

Preprint

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Physiologic Target, Molecular Evolution, and Pathogenic Functions of a Monoclonal Anti–Citrullinated Protein Antibody Obtained From a Patient With Rheumatoid Arthritis

Ozawa

Ouhara

Tsuda

et al. 2020

Arthritis & Rheumatology

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Objective In plasma from a patient with rheumatoid arthritis (RA), we previously isolated a human monoclonal anti–citrullinated protein antibody (ACPA), CCP‐Ab1, that recognizes various citrullinated antigens. In this study, we aimed to explore the physiologic target of CCP‐Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA. Methods The target protein of CCP‐Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline‐reverted (GL‐rev) CCP‐Ab1 was generated, and its reactivity was compared to that of mature CCP‐Ab1. The functions of CCP‐Ab1 and GL‐rev CCP‐Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis–prone SKG mice. Results CCP‐Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL‐rev CCP‐Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (P < 0.05). The elements implicated in GL‐rev CCP‐Ab1 binding to a citrullinated peptide, cfc1‐cyc, were almost identical to those implicated in CCP‐Ab1 binding. In arthritis‐prone SKG mice, CCP‐Ab1, but not GL‐rev CCP‐Ab1, induced significant exacerbation of experimental arthritis (P < 0.05). Increased production of interleukin‐6, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP‐Ab1 compared to those treated with GL‐rev CCP‐Ab1 (P < 0.05). Furthermore, the immune complex formed by CCP‐Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP‐Ab1 (P < 0.05 versus control treatment groups). Conclusion These data show that germline‐encoded CCP‐Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA.

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The role of the complement system in disc degeneration and Modic changes

Heggli,

Teixeira,

Iatridis

et al. 2024

JOR Spine

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Disc degeneration and vertebral endplate bone marrow lesions called Modic changes are prevalent spinal pathologies found in chronic low back pain patients. Their pathomechanisms are complex and not fully understood. Recent studies have revealed that complement system proteins and interactors are dysregulated in disc degeneration and Modic changes. The complement system is part of the innate immune system and plays a critical role in tissue homeostasis. However, its dysregulation has also been associated with various pathological conditions such as rheumatoid arthritis and osteoarthritis. Here, we review the evidence for the involvement of the complement system in intervertebral disc degeneration and Modic changes. We found that only a handful of studies reported on complement factors in Modic changes and disc degeneration. Therefore, the level of evidence for the involvement of the complement system is currently low. Nevertheless, the complement system is tightly intertwined with processes known to occur during disc degeneration and Modic changes, such as increased cell death, autoantibody production, bacterial defense processes, neutrophil activation, and osteoclast formation, indicating a contribution of the complement system to these spinal pathologies. Based on these mechanisms, we propose a model how the complement system could contribute to the vicious cycle of tissue damage and chronic inflammation in disc degeneration and Modic changes. With this review, we aim to highlight a currently understudied but potentially important inflammatory pathomechanism of disc degeneration and Modic changes that may be a novel therapeutic target.

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The involvement of C5a in the progression of experimental arthritis with Porphyromonas gingivalis infection in SKG mice

Cited by 26 publications

References 53 publications

Effect of Porphyromonas gingivalis infection on gut dysbiosis and arthritis exacerbation in mouse model

Effect of Porphyromonas gingivalis infection on gut dysbiosis and arthritis exacerbation in mouse model

Physiologic Target, Molecular Evolution, and Pathogenic Functions of a Monoclonal Anti–Citrullinated Protein Antibody Obtained From a Patient With Rheumatoid Arthritis

The role of the complement system in disc degeneration and Modic changes

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