Imbalance of endotoxin-binding systems in rheumatoid arthritis and association with joint inflammation

Cover Page

Cite item

Full Text

Abstract

this review article analyzes the etiopathogenetic role of endotoxin (lipopolysaccharide, LPS) and the dysfunction of endotoxin-binding systems in the development and progression of rheumatoid arthritis (RA). The aim of this work is to systematize data on the key sources of systemic endotoxin and to characterize the changes in the concentration and functional activity of LPS-binding proteins (LBP, sCD14, BPI) in the systemic circulation and synovial fluid of RA patients. Intestinal dysbiosis, specifically the increased prevalence of Prevotella species, and the impaired integrity of the intestinal epithelial barrier are considered the dominant sources of endotoxemia, forming a pathogenic "gut-joint" axis. Special attention is also given to non-microbial factors, such as smoking, as an additional source of LPS. The analysis reveals specific alterations in endotoxin-binding proteins in RA. LBP is shown to actively amplify local inflammation in the joint, while sCD14 serves not only as a marker but also as a direct pro-inflammatory mediator, which is supported by its correlation with disease activity scores. The increase in BPI levels in synovial fluid is considered a compensatory, yet insufficient, response to the local endotoxin burden. The findings underscore the central role of endotoxemia in maintaining systemic and local inflammation in RA, highlighting the potential for developing therapeutic strategies aimed at modulating endotoxin-dependent pathways.

About the authors

A. A Gorlov

Order of the Red Banner of Labor Medical Institute; V.I. Vernadsky Crimean Federal University

ORCID iD: 0000-0001-6597-8550

V. A Beloglazov

Order of the Red Banner of Labor Medical Institute; V.I. Vernadsky Crimean Federal University

ORCID iD: 0000-0001-9640-754X

I. A Yatskov

Order of the Red Banner of Labor Medical Institute; V.I. Vernadsky Crimean Federal University

ORCID iD: 0000-0002-5486-7262

E. S Ageeva

Order of the Red Banner of Labor Medical Institute; V.I. Vernadsky Crimean Federal University

ORCID iD: 0000-0003-4590-3580

E. V Keledzhiyeva

Order of the Red Banner of Labor Medical Institute; V.I. Vernadsky Crimean Federal University

ORCID iD: 0000-0002-1111-5079

References

  1. Smolen J.S., Aletaha D., McInnes I.B. Rheumatoid arthritis // Lancet. 2016. Vol. 388. № 10055. P. 2023 – 2038.
  2. Chaurasia N., Singh A., Singh I.L., Singh T., Tiwari T. Cognitive dysfunction in patients of rheumatoid arthritis // Journal of Family Medicine and Primary Care. 2020. Vol. 9. P. 2219 – 2225.
  3. Lassere M.N., Rappo J., Portek I.J., Sturgess A., Edmonds J.P. How many life years are lost in patients with rheumatoid arthritis? Secular cause-specific and all-cause mortality in rheumatoid arthritis, and their predictors in a long-term Australian cohort study // Internal Medicine Journal. 2013. Vol. 43. P. 66 – 72.
  4. Zhang Z., Gao X., Liu S., et al. Global, regional, and national epidemiology of rheumatoid arthritis among people aged 20-54 years from 1990 to 2021 // Scientific Reports. 2025. Vol. 15. № 10736.
  5. Venetsanopoulou A.I., Alamanos Y., Voulgari P.V., Drosos A.A. Epidemiology and risk factors for rheumatoid arthritis development // Mediterranean Journal of Rheumatology. 2023. Vol. 34. № 4. P. 404 – 413.
  6. Meyer P.W.A., Ally M.M.T.M., Tikly M., Tintinger G., Winchow L.L., Steel H., Anderson R. Tobacco-derived lipopolysaccharide, not microbial translocation, as a potential contributor to the pathogenesis of rheumatoid arthritis // Mediators of Inflammation. 2019. № 4693870.
  7. Lu J., Wang Y., Wu J., Duan Y., Zhang H., Du H. Linking microbial communities to rheumatoid arthritis: focus on gut, oral microbiome and their extracellular vesicles // Frontiers in Immunology. 2025. Vol. 16. № 1503474.
  8. Arya P., Sharma V., Singh P., Thapliyal S., Sharma M. Bacterial endotoxin-lipopolysaccharide role in inflammatory diseases: an overview // Iranian Journal of Basic Medical Sciences. 2025. Vol. 28. № 5. P. 553 – 564.
  9. Won Y., Yang J.I., Park S., Chun J.S. Lipopolysaccharide binding protein and CD14, cofactors of toll-like receptors, are essential for low-grade inflammation-induced exacerbation of cartilage damage in mouse models of posttraumatic osteoarthritis // Arthritis & Rheumatology. 2021. Vol. 73. № 8. P. 1451 – 1460.
  10. Kitchens R.L., Thompson P.A. Modulatory effects of sCD14 and LBP on LPS-host cell interactions // Journal of Endotoxin Research. 2005. Vol. 11. № 4. P. 225 – 229.
  11. Rhee S.H. Lipopolysaccharide: basic biochemistry, intracellular signaling, and physiological impacts in the gut // Intestinal Research. 2014. Vol. 12. № 2. P. 90 – 95.
  12. Srivastava A., Casey H., Johnson N., Levy O., Malley R. Recombinant bactericidal/permeability-increasing protein rBPI21 protects against pneumococcal disease // Infection and Immunity. 2007. Vol. 75. № 1. P. 342 – 349.
  13. Guo S., Al-Sadi R., Said H.M., Ma T.Y. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14 // American Journal of Pathology. 2013. Vol. 182. № 2. P. 375 – 387.
  14. Bernard N.J. Rheumatoid arthritis: Prevotella copri associated with new-onset untreated RA // Nature Reviews Rheumatology. 2014. Vol. 10. № 1. P. 2.
  15. Utrata A., Schmidtner N., Mester P., Schmid S., M?ller M., Pavel V., Buechler C. Plasma lipopolysaccharide-binding protein (LBP) is induced in critically ill females with Gram-negative infections – preliminary study // Infectious Disease Reports. 2025. Vol. 17. № 1 (10).
  16. Abdelsalam N.A., Hegazy S.M., Aziz R.K. The curious case of Prevotella copri // Gut Microbes. 2023. Vol. 15. № 2. № 2249152.
  17. Heidt C., K?mmerer U., Fobker M., R?ffer A., Marquardt T., Reuss-Borst M. Assessment of intestinal permeability and inflammation biomarkers in patients with rheumatoid arthritis // Nutrients. 2023. Vol. 15. № 10. № 2386.
  18. Heumann D., Bas S., Gallay P., Le Roy D., Barras C., Mensi N., Glauser M.P., Vischer T. Lipopolysaccharide-binding protein as a marker of inflammation in synovial fluid of patients with arthritis: correlation with interleukin 6 and C-reactive protein // Journal of Rheumatology. 1995. Vol. 22. № 7. P. 1224 – 1229.
  19. Ayyappan P., Harms R.Z., Seifert J.A., Bemis E.A., Feser M.L., Deane K.D., Demoruelle M.K., Mikuls T.R., Holers V.M., Sarvetnick N.E. Heightened levels of antimicrobial response factors in patients with rheumatoid arthritis // Frontiers in Immunology. 2020. Vol. 11. № 427.
  20. Talib M., Gyebrovszki B., Fodor A., M?sz?ros A., Balog Vir?g K., Barta L.G., Rojkovich B., Nagy G., S?rmay G. PD-L1? regulatory B cells from rheumatoid arthritis patients have impaired function in suppressing IFN-? and IL-21 production // International Journal of Molecular Sciences. 2025. Vol. 26. № 7. № 2998.
  21. Derksen V.F.A.M., Huizinga T.W.J., van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis // Seminars in Immunopathology. – 2017. Vol. 39. № 4. P. 437 – 446.
  22. Sokolova M.V., Schett G., Steffen U. Autoantibodies in rheumatoid arthritis: historical background and novel findings // Clinical Reviews in Allergy & Immunology. 2022. Vol. 63. № 2. P. 138 – 151.
  23. Hailman E., Lichenstein H.S., Wurfel M.M., Miller D.S., Johnson D.A., Kelley M., Busse L.A., Zukowski M.M., Wright S.D. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14 // Journal of Experimental Medicine. 1994. Vol. 179. № 1. P. 269 – 277.
  24. Chen X., Lu J., Bao J., Guo J., Shi J., Wang Y. Adiponectin: a biomarker for rheumatoid arthritis? // Cytokine & Growth Factor Reviews. 2013. Vol. 24. № 1. P. 83 – 89.
  25. Sabry R., El-Madbouly A.A., Abozeid H.E., Hassan M.M. Urinary orosomucoid-2 and soluble CD14 as potential biomarkers for assessment of disease activity in rheumatoid arthritis // Egyptian Journal of Immunology. 2018. Vol. 25. № 2. P. 107 – 116.
  26. Yu S., Nakashima N., Xu B.H., et al. Pathological significance of elevated soluble CD14 production in rheumatoid arthritis // Rheumatology International. 1998. Vol. 17. № 6. P. 237 – 243.
  27. Ichise Y., Saegusa J., Tanaka-Natsui S., Naka I., Hayashi S., Kuroda R., Morinobu A. Soluble CD14 induces pro-inflammatory cytokines in rheumatoid arthritis fibroblast-like synovial cells via Toll-like receptor 4 // Cells. 2020. Vol. 9. № 7. № 1689.
  28. Schultz H., Weiss J.P. The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease // Clinica Chimica Acta. 2007. Vol. 384. № 1-2. P. 12 – 23.
  29. Punzi L., Peuravuori H., Jokilammi-Siltanen A., et al. Bactericidal/permeability-increasing protein and proinflammatory cytokines in synovial fluid of psoriatic arthritis // Clinical and Experimental Rheumatology. 2000. – Vol. 18. № 5. P. 613 – 615.
  30. Paulsen F., Pufe T., Conradi L., et al. Antimicrobial peptides are expressed and produced in healthy and inflamed human synovial membranes // Journal of Pathology. 2002. Vol. 198. № 3. P. 369 – 377.
  31. Jin S., Wetzel D., Schirmer M. Deciphering mechanisms and implications of bacterial translocation in human health and disease // Current Opinion in Microbiology. 2022. Vol. 67. – № 102147.
  32. Lorenz W., Buhrmann C., Mobasheri A., et al. Bacterial lipopolysaccharides form procollagen–endotoxin complexes that trigger cartilage inflammation and degeneration: implications for the development of rheumatoid arthritis // Arthritis Research & Therapy. 2013. Vol. 15. № R111.
  33. Nishimura H., Gogami A., Miyagawa Y., et al. Bactericidal/permeability-increasing protein promotes complement activation for neutrophil-mediated phagocytosis on bacterial surface // Immunology. 2001. Vol. 103. № 4. P. 519 – 525.
  34. Zheng Y., Wei K., Jiang P., Zhao J., Shan Y., Shi Y., Zhao F., Chang C., Li Y., Zhou M., Lv X., Guo S., He D. Macrophage polarization in rheumatoid arthritis: signaling pathways, metabolic reprogramming, and crosstalk with synovial fibroblasts // Frontiers in Immunology. 2024. Vol. 15. № 1394108.
  35. Matsukawa A., Ohkawara S., Maeda T., et al. Production of IL-1 and IL-1 receptor antagonist and the pathological significance in lipopolysaccharide-induced arthritis in rabbits // Clinical and Experimental Immunology. 1993. Vol. 93. № 2. P. 206 – 211.
  36. Paulsen I.W., Munk H.L., Troelsen J.T., Pedersen O.B. Cluster of differentiation 14 (CD14) and lipopolysaccharide-binding protein (LBP) in psoriatic arthritis and spondyloarthritis // Clinical and Experimental Rheumatology. 2021. Vol. 39. № 5. P. 1196.
  37. Spek C.A., Verbon A., Aberson H., et al. Treatment with an anti-CD14 monoclonal antibody delays and inhibits lipopolysaccharide-induced gene expression in humans in vivo // Journal of Clinical Immunology. 2003. Vol. 23. № 2. P. 132 – 140.
  38. Korkosz M., Bukowska-Strakova K., Sadis S., et al. Monoclonal antibodies against macrophage colony-stimulating factor diminish the number of circulating intermediate and nonclassical monocytes in rheumatoid arthritis patients // Blood. 2012. Vol. 119. № 22. P. 5329 – 5330.
  39. Kwan-Morley J., Albert D. B-cell inhibitors as therapy for rheumatoid arthritis: an update // Current Rheumatology Reports. 2007. Vol. 9. № 5. P. 401 – 406.
  40. Kremer J.M., Westhovens R., Leon M., et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig // New England Journal of Medicine. 2003. Vol. 349. № 20. P. 1907 – 1915.
  41. Lai W., Wang C., Lai R., Peng X., Luo J. Lycium barbarum polysaccharide modulates gut microbiota to alleviate rheumatoid arthritis in a rat model // NPJ Science of Food. 2022. Vol. 6. № 1. Article 34.
  42. Seymour B.J., Allen B.E., Kuhn K.A. Microbial mechanisms of rheumatoid arthritis pathogenesis // Current Rheumatology Reports. 2024. Vol. 26. № 4. P. 124 – 132.
  43. Mazaheri-Tehrani S., Rezaei F., Heidari-Hasanabadi S., Malakoutikhah M., Amani-Beni R., Arefian M., Heidari-Beni M., Kelishadi R. Serum lipopolysaccharide-binding protein (LBP) and metabolic syndrome: a systematic review and meta-analysis // Diabetology & Metabolic Syndrome. 2025. Vol. 17. № 1. № 268.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).