Unidirectional and multidirectional changes in the expression of membrane-bound TNF receptors on immunocompetent cells in rheumatoid arthritis and bronchial asthma

Abstract

Introduction. TNF provides control over inflammatory processes in normal conditions and in the development of rheumatoid arthritis (RA) and bronchial asthma (BA). Important regulatory mechanisms are changes in coexpression and expression density of receptors (TNFR1 and TNFR2), which reflect the sensitivity of cells to the action of a mediator and the type of cell response. The question of identifying the expression levels of receptors that are critical for the formation of irreversible changes in the immune system during the development and chronicity of diseases remains open.

Aim of the study was to compare the parameters of expression and coexpression of type 1 and type 2 receptors to TNF on immunocompetent cells in RA and BA patients compared with those of healthy donors and to identify characteristic patterns of parameter changes in chronic inflammatory immune-mediated diseases.

Material and methods. The expression and coexpression of TNFR1 and TNFR2 was determined on mononuclear cells of healthy donors and patients with RA and BA using multicolor flow cytometry. Logistic regression analysis was performed to identify characteristic changes in pathology.

Results. 3 patterns of changes in the expression and co-expression of receptors in diseases have been identified. For 23 indicators, significant changes were demonstrated towards an increase in the levels of expression and co-expression of TNF receptors in both RA and BA, and for 16 indicators – towards a decrease, respectively. 6 parameters had the greatest diagnostic significance, including percent of TNFR1+TNFR2-cells in CD4+, CD4+/CD45RA+, CD8+ populations; percent of TNFR1+TNFR2+-cells in CD19+, CD8+CD45R0+ populations; and number of TNFR1 on CD4+/CD45R0+-cells.

Conclusion. The study made it possible to establish general trends and characteristic patterns of differences in changes in the expression of TNF receptors in immune-mediated di­seases of various etiologies, as well as to establish certain levels of expression associated with a significant increase in the risk of bronchial asthma and rheumatoid arthritis.

Keywords:TNF; TNFR1; TNFR2; receptor expression density; receptor expression level; rheumatoid arthritis; bronchial asthma

For citation: Alshevskaya A.A., Zhukova Yu.V., Lopatnikova Yu.A., Sennikova Yu.A., Shkaruba N.S., Chumasova O.A., Sizikov A.E., Nepomnyashchikh V.M., Demina D.V., Sennikov S.V. Unidirectional and multidirectional changes in the expression of membrane-bound TNF receptors on immunocompetent cells in rheumatoid arthritis and bronchial asthma. Immunologiya. 2022; 43 (6): 632–42. DOI: https://doi.org/10.33029/0206-4952-2022-43-6-632-642 (in Russian)

Funding. The work was performed within a state task «The study of expression indicators of cytokine receptors and their ligands in the formation of functional properties and the type of response of cell populations of various genesis in normal and pathological conditions» registration number in USAIS RDTCW 122011800353-4.

Conflict of interests. The authors declare no conflict of interests.

Authors’ contribution. The concept and design of the study – Alshevskaya A.A., Lopatnikova Yu.A., Sennikov S.V.; data collection and processing of material – Sennikova Yu.A., Shkaruba N.S., Chumasova O.A., Sizikov A.E., Nepomnyashchikh V.M., Demina D.V.; statistical data processing – Alshevskaya A.A., Zhukova Yu.V., Lopatnikova Yu.A.; text writing – Alshevskaya A.A., Zhukova Yu.V., Lopatnikova Yu.A.; editing – Sennikov S.V., approval of the final version of the article – Sennikov S.V.; responsibility for the integrity of all parts of the article – Zhukova Yu.V.

References

1. Varfolomeev E., Vucic D. Intracellular regulation of TNF activity in health and disease. Cytokine. 2018; 101: 26–32. DOI: https://doi.org/10.1016/j.cyto.2016.08.035

2. Fotin-Mleczek M., Henkler F., Samel D., Reichwein M., Hausser A., Parmryd I., Scheurich P., Schmid J.A., Wajant H. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8. J. Cell Sci. 2002; 115 (pt 13): 2757–70. DOI: https://doi.org/10.1242/jcs.115.13.2757

3. Qu Y., Zhao G., Li H. Forward and reverse signaling mediated by transmembrane tumor necrosis factor-alpha and TNF receptor 2: potential roles in an immunosuppressive tumor microenvironment. Front. Immunol. 2017; 8: 1675–82. DOI: https://doi.org/10.3389/fimmu.2017.01675

4. Sennikov S.V., Al’shevskaya A.A., Zhukova Yu.V., Belomestnova I.A., Karaulov A.V., Lopatnikova Yu.A. Expression density of receptors for immunoregulatory mediators as a modulatory component of biological effects of mediators upon cells (part 2). Meditsinskaya immunologiya. 2019; 21 (3): 379–96. DOI: https://doi.org/10.15789/1563-0625-2019-3-379-396 (in Russian)

5. Liu X., Xie X., Ren Y., Shao Z., Zhang N., Li L., Ding X., Zhang L. The role of necroptosis in disease and treatment. MedComm 2021; 2 (4): 730–55. DOI: https://doi.org/10.1002/mco2.108

6. Alshevskaya A., Lopatnikova J., Zhukova J., Chumasova O., Shkaruba N., Sizikov A., Evsegneeva I., Gladkikh V., Karaulov A., Sennikov S.V. Co-Expression profile of TNF membrane-bound receptors type 1 and 2 in rheumatoid arthritis on immunocompetent cells subsets. Int. J. Mol. Sci. 2019; 21 (1): 288–301. DOI: https://doi.org/10.3390/ijms21010288

7. Alshevskaya A., Zhukova J., Kireev F., Lopatnikova J., Evsegneeva I., Demina D., Nepomniashchikch V., Gladkikh V., Karaulov A., Sennikov S. Redistribution of TNF receptor 1 and 2 expression on immune cells in patients with bronchial asthma. Cells. 2022; 11 (11): 1736–49. DOI: https://doi.org/10.3390/cells11111736

8. Rawlings D.J., Metzler G., Wray-Dutra M., Jackson S.W. Altered B cell signalling in autoimmunity. Nat. Rev. Immunol. 2017; 17 (7): 421–36. DOI: https://doi.org/10.1038/nri.2017.24

9. Lin Y.J., Anzaghe M., Schülke S. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells. 2020; 9 (4): 880–923. DOI: https://doi.org/10.3390/cells9040880

10. Wajant H., Siegmund D. TNFR1 and TNFR2 in the control of the life and death balance of macrophages. Front. Cell Dev. Biol. 2019; 7: 91–105. DOI: https://doi.org/10.3389/fcell.2019.00091

11. Li H., Wang H., Sokulsky L., Liu S., Yang R., Liu X, Zhou L., Li J., Huang C., Li F., Lei X., Jia H., Cheng J., Li F., Yang M., Zhang G. Single-cell transcriptomic analysis reveals key immune cell phenotypes in the lungs of patients with asthma exacerbation. J. Allergy. Clin. Immunol. 2021; 147 (3): 941–54. DOI: https://doi.org/10.1016/j.jaci.2020.09.032

12. Talayev V.Yu., Voronina E.V., Svetlova M.V., Zaichenko I.Ye., Babaykina О.N. Effects of interaction between circulating CD4+ CCR6+ T cells and B-lymphocytes. Immunologiya. 2022; 43 (3): 266–76. DOI: https://doi.org/10.33029/0206-4952-2022-43-3-266-276 (in Russian)

13. Blüml S., Scheinecker C., Smolen J.S., Redlich K. Targeting TNF receptors in rheumatoid arthritis. Int. Immunol. 2012; 24 (5): 275–81. DOI: https://doi.org/10.1093/intimm/dxs047

14. Brenner D., Blaser H., Mak T.W. Regulation of tumor necrosis factor signalling: live or let die. Nat. Rev. Immunol. 2015; 15 (6): 362–74. DOI: https://doi.org/10.1038/nri3834

15. Lo C.H., Huber E.C., Sachs J.N. Conformational states of TNFR1 as a molecular switch for receptor function. Protein Sci. 2020; 29 (6): 1401–15. DOI: https://doi.org/10.1002/pro.3829

16. Yan F., Du R., Wei F., Zhao H., Yu J., Wang C., Zhan Z., Ding T., Ren X., Chen X., Li H. Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients. Cancer Immunol. Immunother. 2015; 64 (11): 1475–85. DOI: https://doi.org/10.1007/s00262-015-1751-z

17. Wang L., Netto KG., Zhou L., Liu X., Wang M., Zhang G., Foster P.S., Li F., Yang M. Single-cell transcriptomic analysis reveals the immune landscape of lung in steroid-resistant asthma exacerbation. Proc. Natl Acad. Sci. USA. 2021; 118 (2): e2005590118. DOI: https://doi.org/10.1073/pnas.2005590118

18. Ren P., Lu L., Cai S., Chen J., Lin W., Han F. Alternative splicing: a new cause and potential therapeutic target in autoimmune disease. Front. Immunol. 2021; 12: 713540. DOI: https://doi.org/10.3389/fimmu.2021.713540

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