Imbalance of lipopolysaccharide-binding systems as a potential link in pathogenesis of rheumatoid arthritis

Lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria is a strong activator of innate immune system and inducer of systemic and local inflammation. Due to increasing number of factors contributing to the translocation of LPS into the systemic bloodstream, e.g., non-adequate antibiotic therapy, usage of entero- and hepatotoxic drugs, as well as increased proportion of carbohydrate and fatty foods in the diet of modern people, the role of LPS is growing, in view of maintaining low-grade inflammatory background. Interactions of endotoxin within human body are mediated by a number of receptors and carrier molecules, many of which can be distinguished into a group of so-called “LPS-binding systems”, i.e., lipopolysaccharidebinding protein (LBP) and bactericidal/permeability-increasing protein (BPI). The character of response to increased LPS pool in blood circulation depends largely on these molecules, as well as additional substances that interact with LPS and LPS-binding systems, in particular, low-density lipoproteins (LDL) and high-density lipoproteins (HDL). Given current publications reporting elevated LPS levels in patients with rheumatoid arthritis (RA), and persistence of dyslipidemias in the vast majority of these patients, LPS is potentially a pathogenetically important factor in RA. This review presents basic data on the biology and role of LPS and “lipopolysaccharide-binding systems” in development and maintenance of inflammation state in RA. Information was searched using the keywords “rheumatoid arthritis and lipopolysaccharide”, “rheumatoid arthritis and lipopolysaccharide-binding protein”, “rheumatoid arthritis and BPI” in foreign and Russian scientific databases, including e-Library and PubMed. The presented data allow us to consider the combination of “lipopolysaccharide-binding systems” imbalance and dyslipidemia a sufficient aggravating pro-inflammatory factor in RA, and the search for potential mechanisms influencing these conditions, either separately, or in combined manner, as a promising field for clinical research.

1. Galushko E.A., Nasonov E.L. Prevalence of rheumatic diseases in Russia. Almanakh klinicheskoy meditsiny = Almanac of Clinical Medicine, 2018, Vol. 46, no. 1, pp. 32-39. (In Russ.)

2. Epifantseva N.V., Emelyanova A.N., Kalinina E.N., Karavaeva T.M. Level of lipopolysaccharide-binding protein in acute intestinal infections and the effect of interleukins-1β and -10 on its synthesis. Kazanskiy meditsinskiy zhurnal = Kazan Medical Journal, 2020. no. 4, pp. 590-594. (In Russ.)

3. Kunst M.A., Yakupovha S.P., Zinkevich O.D., Abdrakipov R.Z., Afanasyeva M.A., Sukhorukova E.V. Role of microbial infection and intestinal permeability in the pathogenesis of rheumatoid arthritis. Prakticheskaya meditsina = Practical Medicine, 2014, no. 4, pp. 54-58. (In Russ.)

4. Matveichev A.V., Talaev V.Y., Evplova I.A. Physiology and functioning of T-helper type 17. Uspekhi sovremennoy biologii = Biology Bulletin Reviews, 2016, Vol. 136, no. 3, pp. 285-300. (In Russ.)

5. Saidov M.Z. Autophagy, apoptosis, necroptosis, pyroptosis and netosis in the pathogenesis of immune-inflammatory rheumatic diseases. Meditsinskaya immunologiya = Medical Immunology (Russia), 2022, Vol. 24, no. 4, pp. 659-704. (In Russ.) doi: 10.15789/1563-0625-AAN-2482.

6. Yakovlev M.Yu. “Endotoxin aggression” as a pre-disease or a universal factor in the pathogenesis of human and animal diseases. Uspekhi sovremennoy biologii = Biology Bulletin Reviews, 2003, Vol. 123, no. 1, pp. 31-40. (In Russ.).

7. Abdollahi-Roodsaz S., Joosten L.A., Koenders M.I., Devesa I., Roelofs M.F., Radstake T.R., HeuvelmansJacobs M., Akira S., Nicklin M.J., Ribeiro-Dias F., van den Berg W.B. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J. Clin. Invest., 2008, Vol. 118, no. 1, pp. 205-216.

8. Alam J., Jantan I., Bukhari S.N.A. Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy. Biomed. Pharmacother., 2017, Vol. 92, pp. 615-633.

9. Alexander C., Rietschel Е.Т. Bacterial lipopolysaccharides and innate immunity. J. Endotoxin Res., 2001, Vol. 7, no. 3, pp. 167-202.

10. Alivernini S., Firestein G.S., McInnes I.B. The pathogenesis of rheumatoid arthritis. Immunity, 2022, Vol. 55, no. 12, pp. 2255-2270.

11. Ancochea J., Girón R.M., López-Botet M. Production of tumor necrosis factor alpha and interleukin-6 by alveolar macrophages from patients with rheumatoid arthritis and interstitial pulmonary disease. Arch. Bronconeumol., 1997, Vol. 33, no. 7-8, pp. 335-340. (In Spanish)

12. Arditi M., Zhou J., Huang S.H., Luckett P.M., Marra M.N., Kim K.S. Bactericidal/permeability-increasing protein protects vascular endothelial cells from lipopolysaccharide-induced activation and injury. Infect. Immun., 1994, Vol. 62, no. 9, pp. 3930-3936.

13. Arvikar S.L., Collier D.S., Fisher M.C., Unizony S., Cohen G.L., McHugh G., Kawai T., Strle K., Steere A.C. Clinical correlations with Porphyromonas gingivalis antibody responses in patients with early rheumatoid arthritis. Arthritis Res. Ther., 2013, Vol. 15, R109. doi: 10.1186/ar4289.

14. Bjorstad A., Brown K., Forsman H., Dahlgren C., Karlsson-Bengtsson A., Bylund J. Antimicrobial host defence peptides of human neutrophils – roles in innate immunity. Antiinfect Agents Med Chem, 2008, Vol. 7, pp. 155-168.

15. Cho M.L., Jung Y.O., Kim K.W., Park M.K., Oh H.J., Ju J.H., Cho Y.G., Min J.K., Kim S.I., Park S.H., Kim H.Y. IL-17 induces the production of IL-16 in rheumatoid arthritis. Exp. Mol. Med., 2008, Vol. 40, pp. 237-245.

16. Chovanova L., Vlcek M., Krskova K., Penesova A., Radikova Z., Rovensky J., Cholujova D., Sedlák J., Imrich R. Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears from patients with rheumatoid arthritis. Gen. Physiol. Biophys., 2013, Vol. 32, pp. 395-404.

17. Chuang H.C., Chen M.H., Chen Y.M., Yang H.Y., Ciou Y.R., Hsueh C.H., Tsai C.Y., Tan T.H. BPI overexpression suppresses Treg differentiation and induces exosome-mediated inflammation in systemic lupus erythematosus. Theranostics, 2021, Vol. 11, no. 20, pp. 9953-9966.

18. Currie C.G., McCallum K., Poxton І.R. Mucosal and systemic antibody responses to the lipopolysaccharide of Esherichia coli 0157 in health and disease. J. Med. Microbiol., 2001, Vol. 50, no. 4, pp. 345-354.

19. Detert J., Pischon N., Burmester G.R., Buttgereit F. The association between rheumatoid arthritis and periodontal disease. Arthritis Res. Ther., 2010, Vol. 12, no. 5, 218. doi: 10.1186/ar3106.

20. Ederer K.U., Holzinger J.M., Maier K.T., Zeller L., Werner M., Toelge M., Gessner A., Bülow S. A polymorphism of bactericidal/permeability-increasing protein affects its neutralization efficiency towards lipopolysaccharide. Int. J. Mol. Sci., 2022, Vol. 23, no. 3, 1324. doi: 10.3390/ijms23031324.

21. Elsbach P., Weiss J. The bactericidal/permeability-increasing protein (BPI), a potent element in host-defense against gram-negative bacteria and lipopolysaccharide. Immunobiology, 1993, Vol. 187, no. 3-5, pp. 417-429.

22. Erridge C., Bennett-Guerrero E., Poxton I.R. Structure and function of lipopolysaccharides. Microbes Infect., 2002, Vol. 4, no. 8, pp. 837-851.

23. Fabris M., Tolusso B., Di Poi E., Tomietto P., Sacco S., Gremese E., Ferraccioli G. Mononuclear cell response to lipopolysaccharide in patients with rheumatoid arthritis: relationship with tristetraprolin expression. J. Rheumatol., 2005, Vol. 32, no. 6, pp. 998-1005.

24. Fabris M., Tolusso B., Gremese E., Tomietto P., Ferraccioli G. Analysis of the kinetic of expression of tristetraprolin and HuR by rheumatoid arthritis patients pheripheral blood mononuclear cells stimulated with lipopolysaccharide. Reumatismo, 2004, Vol. 56, no. 2, pp. 94-103.

25. Gomes R.P., Bressan E., da Silva T.M., Gevaerd M. da S., Tonussi C.R., Domenech S.C. Effects of one minute and ten minutes of walking activity in rats with arthritis induced by complete Freund’s adjuvant on pain and edema symptoms. Rev. Bras. Reumatol., 2014, Vol. 54, no. 2, pp. 83-89.

26. Gangloff S.C., Zähringer U., Blondin C., Guenounou M., Silver J., Goyert S.M. Influence of CD14 on Ligand Interactions between Lipopolysaccharide and Its Receptor complex. J. Immunol., 2005, Vol. 175, no. 11, pp. 3940-3945.

27. Hardardottir I., Grunfeld C., Feingold K.R. Effects of endotoxin and cytokines on lipid metabolism. Curr. Opin. Lipidol., 1994, Vol. 5, pp. 207-215.

28. Heinzelmann M., Bosshart H. Heparin Binds to Lipopolysaccharide (LPS)-binding protein, facilitates the transfer of LPS to CD14, and enhances LPS-induced activation of peripheral blood monocytes. J. Immunol., 2005, Vol. 174, no. 4, pp. 2280-2287.

29. Huang Q., Ma Y., Adebayo A., Pope R.M. Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis. Arthritis Rheum., 2007, Vol. 56, pp. 2192-2201.

30. Huang Z.Y., Stabler T., Pei F.X., Kraus V.B. Both systemic and local lipopolysaccharide (LPS) burden are associated with knee OA severity and inflammation. Osteoarthritis Cartilage, 2016, Vol. 24, Iss. 10, pp. 1769-1775.

31. James C. Diagnosis of endotoxemia with gram-negative bacteremia is bacterial species dependent: a metaanalysis of clinical studies. J. Clin. Microbiol., 2009, Vol. 47, no. 12, pp. 3826-3831.

32. Jin W., Dong C. IL-17 cytokines in immunity and inflammation. Emerg. Microbes Infect., 2013, Vol. 2, no. 9, e60. doi: 10.1038/emi.2013.58.

33. Jung Y.O., Cho M.L., Lee S.Y., Oh H.J., Park J.S., Park M.K., Park M.J., Ju J.H., Kim S.I., Park S.H., Kim H.Y., Min J.K. Synergism of toll-like receptor 2 (TLR2), TLR4, and TLR6 ligation on the production of tumor necrosis factor (TNF)-alpha in a spontaneous arthritis animal model of interleukin (IL)-1 receptor antagonist-deficient mice. Immunol. Lett., 2009, Vol. 123, no. 2, pp. 138-143.

34. Kellner H. Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential. Ther. Adv. Musculoskelet. Dis., 2013, Vol. 5, no. 3, pp. 141-152.

35. Kitchens R.L., Thompson P.A. Modulatory effects of sCD14 and LBP on LPS-host cell interactions. J. Endotoxin Res., 2005, Vol. 11, no. 4, pp. 225-229.

36. Levels J.H.M., Marquart J.A., Abraham P.R., van den Ende A.E., Molhuizen H.O.F., van Deventer S.J.H., Meijers J.C.M. Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein. Infect. Immun., 2005, Vol. 73, no. 4, pp. 2321-2326.

37. Levin M., Quint P., Goldstein B., Barton R., Bradley J., Shemie S., Yeh T., Kim S., Cafaro D., Scannon P., Giroir B. Recombinant bactericidal/permeability-increasing protein (rBPI 21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. Lancet, 2000, Vol. 356, pp. 961-967.

38. Levy O. A Neutrophil-Derived Anti-Infective Molecule: Bactericidal/Permeability-Increasing Protein. Antimicrob. Agents Chemother., 2000, Vol. 44, no. 11, pp. 2925-2931.

39. Levy O., Sisson R.B., Kenyon J., Eichenwald E., Macone A.B., Goldmann D. Enhancement of neonatal innate defense: effects of adding an N-terminal recombinant fragment of bactericidal/permeability-increasing protein on growth and tumor necrosis factor-inducing activity of gram-negative bacteria tested in neonatal cord blood ex vivo. Infect. Immun., 2000, Vol. 68, no. 9, pp. 5120-5125.

40. Lorenz W., Buhrmann C., Mobasheri A., Lueders C., Shakibaei M. Bacterial lipopolysaccharides form procollagen-endotoxin complexes that trigger cartilage inflammation and degeneration: implications for the development of rheumatoid arthritis. Arthritis Res. Ther., 2013, Vol. 15, R111. doi: 10.1186/ar4291.

41. Lubberts E., Joosten L.A., Oppers B., van den Bersselaar L., Coenen-de Roo C.J., Kolls J.K., Schwarzenberger P., van de Loo F.A., van den Berg W.B. IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J. Immunol., 2001, Vol. 167, no. 2, pp. 1004-1013.

42. Mangat Р., Wegner N., Venables P.J., Potempa J. Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis? Arthritis Res. Ther., 2010, Vol. 12, no. 3, 209. doi: 10.1186/ar3000.

43. Marra M.N., Wilde C.G., Griffith J.E., Snable J.L., Scott R.W. Bactericidal/permeability-increasing protein has endotoxin-neutralizing activity. J. Immunol., 1990, Vol. 144, no. 2, pp. 662-666.

44. McAleer J.P., Liu B., Li Z., Ngoi S.M., Dai J., Oft M., Vella A.T. Potent intestinal Th17 priming through peripheral lipopolysaccharide-based immunization. J. Leukoc. Biol., 2010, Vol. 88, no. 1, pp. 21-31.

45. McInnes I.B., Buckley C.D., Isaacs J.D. Cytokines in rheumatoid arthritis – shaping the immunological landscape. Nat. Rev. Rheumatol., 2016, Vol. 12, no. 1, pp. 63-68.

46. Meszaros K., Aberle S., Dedrick R., Machovich R., Horwitz A., Birr C., Theofan G., Parent J.B. Monocyte tissue factor induction by lipopolysaccharide (LPS): dependence on LPS-binding protein and CD14, and inhibition by a recombinant fragment of bactericidal/permeability-increasing protein. Blood, 1994, Vol. 83, no. 9, pp. 2516-2525.

47. Mills K.H.G. IL-17 and IL-17-producing cells in protection versus pathology. Nat. Rev. Immunol., 2023, Vol. 23, pp. 38-54.

48. Modi D.K., Chopra V.S., Bhau U. Rheumatoid arthritis and periodontitis: biological links and the emergence of dual purpose therapies. Indian J. Dent Res., 2009, Vol. 20, no. 1, pp. 86-90.

49. Nair A., Kanda V., Bush-Joseph C., Verma N., Chubinskaya S., Mikecz K., Glant T.T., Malfait A.M., Crow M.K., Spear G.T., Finnegan A., Scanzello C.R. Synovial fluid from patients with early osteoarthritis modulates fibroblast-like synoviocyte responses to toll-like receptor 4 and toll-like receptor 2 ligands via soluble CD14. Arthritis Rheum., 2012, Vol. 64, no. 7, pp. 2268-2277.

50. Ooi C.E., Weiss J., Doerfler M.E., Elsbach P. Endotoxin-neutralizing properties of the 25 kD N-terminal fragment and a newly isolated 30 kD C-terminal fragment of the 55-60 kD bactericidal/permeability-increasing protein of human neutrophils. J. Exp. Med., 1991, Vol. 174, no. 3, pp. 649-655.

51. Panayi G.S. B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology, 2005, Vol. 44, Suppl. 2, pp. 113-117.

52. Park J.H., Jeong S.Y., Choi A.J., Kim S.J. Lipopolysaccharide directly stimulates Th17 differentiation in vitro modulating phosphorylation of RelB and NF-κB1. Immunol. Lett., 2015, Vol. 165, no. 1, pp. 10-19.

53. Qin Y., Chen Y., Wang W., Wang Z., Tang G., Zhang P., He Z., Liu Y., Dai S.M., Shen Q. HMGB1-LPS complex promotes transformation of osteoarthritis synovial fibroblasts to a rheumatoid arthritis synovial fibroblastlike phenotype. Cell Death Dis., 2014, Vol. 5, e1077. doi: 10.1038/cddis.2014.48.

54. Rafael-Vidal C., Pérez N., Altabás I., Garcia S., Pego-Reigosa J.M. Blocking IL-17: A promising strategy in the treatment of systemic rheumatic diseases. Int. J. Mol. Sci., 2020, Vol. 21, no. 19, 7100. doi: 10.3390/ijms21197100.

55. Scanu A., Luisetto R., Oliviero F., Galuppini F., Lazzarin V., Pennelli G., Masiero S., Punzi L. Bactericidal/permeability-increasing protein downregulates the inflammatory response in in vivo models of arthritis. Int. J. Mol. Sci., 2022, Vol. 23, 13066. doi: 10.3390/ijms232113066.

56. Schultz H., Weiss J.P. The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease. Clin. Chim. Acta, 2007, Vol. 384, no. 1-2, pp. 12-23.

57. Sinkeviciute D., Aspberg A., He Y., Bay-Jensen A.C., Önnerfjord P. Characterization of the interleukin-17 effect on articular cartilage in a translational model: an explorative study. BMC Rheumatol., 2020, Vol. 4, 30. doi: 10.1186/s41927-020-00122-x.

58. Snelling S.J.B., Bas S., Puskas G.J., Dakin S.G., Suva D., Finckh A., Gabay С., Hoffmeyer P., Carr A.J., Lübbeke A. Presence of IL-17 in synovial fluid identifies a potential inflammatory osteoarthritic phenotype. PLoS One, 2017, Vol. 12, no. 4, e0175109. doi: 10.1371/journal.pone.0175109.

59. Stierschneider A., Neuditschko B., Colleselli K., Hundsberger H., Herzog F., Wiesner C. Comparative and temporal characterization of LPS and blue-light-induced TLR4 signal transduction and gene expression in optogenetically manipulated endothelial cells. Cells, 2023, Vol. 12, no. 5, 697. doi: 10.3390/cells12050697.

60. Tobias P.S., Soldau K., Iovine N.M., Elsbach P., Weiss J. Lipopolysaccharide (LPS)-binding proteins BPI and LBP form different types of complexes with LPS. J. Biol. Chem., 1997, 272, Iss. 30, pp. 18682-18685.

61. van der Heijden I.M., Wilbrink B., Tchetverikov I., Schrijver I.A., Schouls L.M., Hazenberg M.P., Breedveld F.C., Tak P.P. Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides. Arthritis Rheum., 2000, Vol. 43, no. 3, pp. 593-598.

62. Vesy C.J., Kitchens R.L., Wolfbauer G., Albers J.J., Munford R.S. Lipopolysaccharide-binding protein and phospholipid transfer protein release lipopolysaccharides from gram-negative bacterial membranes. Infect. Immun., 2000, Vol. 68, no. 5, pp. 2410-2417.

63. Wang P.L., Ohura K. Porphyromonas gingivalis lipopolysaccharide signaling in gingival fibroblasts-CD14 and Toll-like receptors. Crit. Rev. Oral Biol. Med., 2002, Vol. 13, no. 1, pp. 132-142.

64. Weiss J. Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP): structure, function and regulation in host defence against Gram-negative bacteria. Biochem. Soc. Trans., 2003, Vol. 31, no. 4, pp. 785-790.

65. Wilde C.G., Seilhamer J.J., McGrogan M., Ashton N., Snable J.L., Lane J.C., Leong S.R., Thornton M.B., Miller K.L., Scott R.W. Bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein. LPS binding properties and effects on LPS-mediated cell activation. J. Biol. Chem., 1994, Vol. 269, no. 26, pp. 17411-17416.

66. Wittmann I., Schönefeld M., Aichele D., Groer G., Gessner A., Schnare M. Murine bactericidal/permeabilityincreasing protein inhibits the endotoxic activity of lipopolysaccharide and gram-negative bacteria. J. Immunol., 2008, Vol. 180, no. 11, pp. 7546-7552.

67. Wright S.D., Ramos R.A., Tobias P.S., Ulevitch R.J., Mathison J.C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science, 1990, Vol. 249, no. 4975, pp. 1431-1433.

68. Yamashita M. Bactericidal/permeability-increasing protein ameliorates hypercoagulability after hemorrhagic shock. Thromb. Res., 1997, Vol. 87, Iss. 3, pp. 323-329.

69. Yang M., Hase H. B cell maturation antigen, the receptor for a proliferation-inducing ligand and B cell-activating factor of the TNF family, induces antigen presentation in B cells. J. Immunol., 2005, Vol. 175, pp. 2814-2824.

70. Yu S., Nakashima N., Xu B.H., Matsuda T., Izumihara A., Sunahara N., Nakamura T., Tsukano M., Matsuyama T. Pathological significance of elevated soluble CD14 production in rheumatoid arthritis: in the presence of soluble CD14, lipopolysaccharides at low concentrations activate RA synovial fibroblasts. Rheumatol. Int, 1998, Vol. 17, no. 6, pp. 237-243.