The role of the CX3CL1/CX3CR1 axis as potential inflammatory biomarkers in subjects with periodontitis and rheumatoid arthritis: A systematic review

Abstract

Objective: This systematic review aimed to investigate the role of the C-X3-C motif ligand 1/chemokine receptor 1 C-X3-C motif (CX3CL1/CX3CR1) axis in the pathogenesis of periodontitis. Furthermore, as a secondary objective, we determine whether the CX3CL1/CX3CR1 axis could be considered complementary to clinical parameters to distinguish between periodontitis and rheumatoid arthritis (RA) and/or systemically healthy subjects.

Methods: The protocol used for this review was registered in OSF (10.17605/OSF.IO/KU8FJ). This study was designed following Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Records were identified using different search engines (PubMed/MEDLINE, Scopus, Science Direct, and Web of Science) from August 10, 2006, to September 15, 2023. The observational studies on human subjects diagnosed with periodontitis and RA and/or systemically healthy were selected to analyze CX3CL1 and CX3CR1 biomarkers. The methodological validity of the selected articles was assessed using NIH.

Results: Six articles were included. Biological samples (gingival crevicular fluid [GCF], saliva, gingival tissue biopsies, serum) from 379 subjects (n = 275 exposure group and n = 104 control group) were analyzed. Higher CX3CL1 and CX3CR1 chemokine levels were found in subjects with periodontitis and RA compared with periodontal and systemically healthy subjects.

Conclusion: Very few studies highlight the role of the CX3CL1/CX3CR1 axis in the pathogenesis of periodontitis; however, increased levels of these chemokines are observed in different biological samples (GCF, gingival tissue, saliva, and serum) from subjects with periodontitis and RA compared with their healthy controls. Future studies should focus on long-term follow-up of subjects and monitoring changes in cytokine levels before and after periodontal therapy to deduce an appropriate interval in health and disease conditions.

Keywords: CX3CL1; CX3CR1; biomarkers of inflammation; chemokines; fractalkine; periodontitis; rheumatoid arthritis.

Figure 1

Clinical, genetic, microbiological, and immunological characteristics that subjects with periodontitis and rheumatoid arthritis (RA) share with each other., Both diseases are chronic and characterized by the presence of inflammation and destruction of the previously mentioned tissues. Genetically, the highly polymorphic HLA‐DRB1 (shared epitope, SE) locus represents the most strongly involved genetic factor related to susceptibility and severity in developing both diseases. Concerning microbiological factors, clinical studies indicate that subjects with periodontitis and Porphyromonas gingivalis infection are at risk of developing RA. In addition, in subjects with periodontitis and/or RA, increased levels of pro‐inflammatory cytokines (TNF, IL‐1, IL‐6, MMP) and antibodies such as ACPA have been observed. Abbreviations: ACPA, anti‐citrullinated protein antibodies; HLA‐DRB1, human leukocyte antigen; IL1, interleukin‐1; IL‐6 Interleukin‐6; KCNQ1, cardiac potassium channels; MMPs, matrix metalloproteinases; TNF, tumor necrosis factor.

Figure 2

Immunological interactions between periodontitis and rheumatoid arthritis. IL, interleukin; MMPS, matrix metalloproteinases; RANKL, receptor activator of nuclear factor κ‐Β ligand; TNF‐α, tumor necrosis factor‐α.

Figure 3

PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic and Meta‐Analyses.