MicroRNAs Targeting Programmed Cell Death Protein 1 (PD-1) Promote Natural Killer Cell Exhaustion in Rheumatoid Arthritis
-
Maryam Hemmatzadeh
,
Elham Ahangar Parvin
,
Alireza Ghanavatinejad
,
Narges Rostami
,
Mehrzad Hajaliloo
,
Navid Shomali
,
Hamed Mohammadi
,
Farhad Jadidi-Niaragh
Abstract
Natural killer (NK) cells play a role in the pathogenesis of rheumatoid arthritis (RA). Upregulated levels of programmed cell death protein 1 (PD-1) is a sign of exhausted NK cells that could be regulated by microRNAs (miRNAs). In this investigation, we determined PD‑1 expression on NK cells (as a representation of NK cell exhaustion) in RA patients and evaluated if miRNAs are involved in the modulation of PD-1 expression in NK cells.
Peripheral blood specimens were obtained from 40 RA patients and 20 healthy subjects. NK cells were isolated by negative selection from a pool of peripheral blood mononuclear cells. The frequency of PD-1–expressing NK cells and the expression of PD-1 on NK cells were analyzed by flow cytometry. Real-time PCR was used to measure the expression levels of PD-1 mRNA and miRNAs in the NK cells.
The percentage of the PD-1–expressing NK cells and Mean fluorescence intensity (MFI) of PD-1 expression on the NK cells were significantly higher in the RA cases compared to the controls. The mRNA expression of PD-1 was significantly upregulated in NK cells from RA patients compared to healthy subjects. The expression levels of miR-28, miR-138, and miR-4717 were significantly downregulated in the NK cells from RA patients compared to the healthy group.
In RA, miRNAs probably regulate the NK cell exhaustion process through driving PD-1 expression.
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3. Kronzer VL, Davis JM. Etiologies of rheumatoid arthritis: update on mucosal, genetic, and cellular pathogenesis. Curr Rheumatol Rep. 2021;23(4):1-10.
4. Ahern DJ, Brennan FM. The role of Natural Killer cells in the pathogenesis of rheumatoid arthritis: major contributors or essential homeostatic modulators? Immunol lett. 2011;136(2):115-21.
5. Mohammadi H, Sharafkandi N, Hemmatzadeh M, Azizi G, Karimi M, Jadidi-Niaragh F, et al. The role of innate lymphoid cells in health and disease. J Cell Physiol. 2018;233(6):4512-29.
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7. Afshar B, Khalifehzadeh-Esfahani Z, Seyfizadeh N, Rezaei Danbaran G, Hemmatzadeh M, Mohammadi H. The role of immune regulatory molecules in multiple sclerosis. J Neuroimmunol. 2019;337:577061.
8. Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent antitumor immunity. Nat Immunol. 2018;19(7):723-32.
9. Patsoukis N, Wang Q, Strauss L, Boussiotis VA. Revisiting the PD-1 pathway. Sci Advances. 2020;6(38):eabd2712.
10. Beldi-Ferchiou A, Caillat-Zucman S. Control of NK cell activation by immune checkpoint molecules. Int J Mol Sciences. 2017;18(10):2129.
11. Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, et al. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization. J Allergy Clin Immunol. 2017;139(1):335-46. e3.
12. Alvarez M, Simonetta F, Baker J, Morrison AR, Wenokur AS, Pierini A, et al. Indirect impact of PD-1/PD-L1 blockade on a murine model of NK cell exhaustion. Front Immunol. 2020:7.
13. Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze‐Koops H, et al. Role of Th17 cells in human autoimmune arthritis. Arthritis & Rheumatism. 2010;62(10):2876-85.
14. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature. 2000;408(6812):600-5.
15. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123-32.
16. Shen Q, Beucler MJ, Ray SC, Rappleye CA. Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens. PLoS Pathogens. 2018;14(11):e1007444.
17. Dalbeth N, Callan MF. A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2002;46(7):1763-72.
18. Romas E, Gillespie M, Martin T. Involvement of receptor activator of NFκB ligand and tumor necrosis factor-α in bone destruction in rheumatoid arthritis. Bone. 2002;30(2):340-6.
19. Hojjatipour T, Aslani S, Salimifard S, Mikaeili H, Hemmatzadeh M, Gholizadeh Navashenaq J, et al. NK cells - Dr. Jekyll and Mr. Hyde in autoimmune rheumatic diseases. Int Immunopharmacol. 2022;107:108682.
20. Shomali N, Suliman Maashi M, Baradaran B, Daei Sorkhabi A, Sarkesh A, Mohammadi H, et al. Dysregulation of survivin-targeting microRNAs in autoimmune diseases: new perspectives for novel therapies. Front Immunol. 2022:848.
21. Diener C, Keller A, Meese E. Emerging concepts of miRNA therapeutics: From cells to clinic. Trends in Genetics. 2022.
22. Swingler T, Niu L, Smith P, Paddy P, Le L, Barter M, et al. The function of microRNAs in cartilage and osteoarthritis. Clin Exp Rheumatol. 2019;37(5):40-7.
23. Saidi N, Ghalavand M, Hashemzadeh MS, Dorostkar R, Mohammadi H, Mahdian-Shakib A. Dynamic changes of epigenetic signatures during chondrogenic and adipogenic differentiation of mesenchymal stem cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2017;89:719-31.
24. Ebrahimiyan H, Rezaei N, Vojdanian M, Aslani S, Jamshidi A, Mahmoudi M. microRNA involvement in the regulation of survivin in peripheral blood mononuclear cells from rheumatoid arthritis patients. Int J Rheumatic Dis. 2019;22(6):1107-14.
25. Pesce S, Greppi M, Ferretti E, Obino V, Carlomagno S, Rutigliani M, et al. miRNAs in NK cell-based immune responses and cancer immunotherapy. Front Cell Develop Biol. 2020;8:119.
26. Li Q, Johnston N, Zheng X, Wang H, Zhang X, Gao D, et al. miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion. Oncotarget. 2016;7(33):53735.
27. Wei J, Nduom EK, Kong L-Y, Hashimoto Y, Xu S, Gabrusiewicz K, et al. MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. Neuro Oncol. 2016;18(5):639-48.
28. Zhang G, Li N, Li Z, Zhu Q, Li F, Yang C, et al. microRNA-4717 differentially interacts with its polymorphic target in the PD1 3′ untranslated region: A mechanism for regulating PD-1 expression and function in HBV-associated liver diseases. Oncotarget. 2015;6(22):18933.
29. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis & rheumatism. 2010;62(9):2569-81.
30. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8.
31. Yamin R, Berhani O, Peleg H, Aamar S, Stein N, Gamliel M, et al. High percentages and activity of synovial fluid NK cells present in patients with advanced stage active Rheumatoid Arthritis. Sci Reports. 2019;9(1):1-12.
32. Lin S-J, Hsu C-Y, Kuo M-L, Lee P-T, Hsiao H-S, Chen J-Y. Phenotypic and functional characterization of natural killer cells in rheumatoid arthritis-regulation with interleukin-15. Sci Reports. 2020;10(1):1-8.
33. Aramaki T, Ida H, Izumi Y, Fujikawa K, Huang M, Arima K, et al. A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis. Modern Rheumatol. 2009;19(3):245-52.
34. Richter J, Benson V, Grobarova V, Svoboda J, Vencovsky J, Svobodova R, et al. CD161 receptor participates in both impairing NK cell cytotoxicity and the response to glycans and vimentin in patients with rheumatoid arthritis. Clin Immunol. 2010;136(1):139-47.
35. Leavenworth JW, Wang X, Wenander CS, Spee P, Cantor H. Mobilization of natural killer cells inhibits development of collagen-induced arthritis. Proc Nat Academy Sci. 2011;108(35):14584-9.
36. Thanapati S, Ganu M, Giri P, Kulkarni S, Sharma M, Babar P, et al. Impaired NK cell functionality and increased TNF-α production as biomarkers of chronic chikungunya arthritis and rheumatoid arthritis. Hum Immunol. 2017;78(4):370-4.
37. Söderström K, Stein E, Colmenero P, Purath U, Müller-Ladner U, De Matos CT, et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Nat Acad Sci. 2010;107(29):13028-33.
38. De Matos CT, Berg L, Michaëlsson J, Felländer‐Tsai L, Kärre K, Söderström K. Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion. Immunology. 2007;122(2):291-301.
39. Nielsen N, Pascal V, Fasth AE, Sundström Y, Galsgaard ED, Ahern D, et al. Balance between activating NKG 2D, DNAM‐1, NK p44 and NK p46 and inhibitory CD 94/NKG 2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts. Immunology. 2014;142(4):581-93.
40. Chen J, Yang J, Qiao Y, Li X. Understanding the Regulatory Roles of Natural Killer T Cells in Rheumatoid Arthritis: T Helper Cell Differentiation Dependent or Independent? Scandinavian J Immunol. 2016;84(4):197-203.
41. Li Q, Johnston N, Zheng X, Wang H, Zhang X, Gao D, et al. miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion. Oncotarget. 2016;7(33):53735-50.
42. Zhang G, Li N, Li Z, Zhu Q, Li F, Yang C, et al. microRNA-4717 differentially interacts with its polymorphic target in the PD1 3' untranslated region: A mechanism for regulating PD-1 expression and function in HBV-associated liver diseases. Oncotarget. 2015;6(22):18933-44.
2. Philippou E, Petersson SD, Rodomar C, Nikiphorou E. Rheumatoid arthritis and dietary interventions: systematic review of clinical trials. Nut Rev. 2021;79(4):410-28.
3. Kronzer VL, Davis JM. Etiologies of rheumatoid arthritis: update on mucosal, genetic, and cellular pathogenesis. Curr Rheumatol Rep. 2021;23(4):1-10.
4. Ahern DJ, Brennan FM. The role of Natural Killer cells in the pathogenesis of rheumatoid arthritis: major contributors or essential homeostatic modulators? Immunol lett. 2011;136(2):115-21.
5. Mohammadi H, Sharafkandi N, Hemmatzadeh M, Azizi G, Karimi M, Jadidi-Niaragh F, et al. The role of innate lymphoid cells in health and disease. J Cell Physiol. 2018;233(6):4512-29.
6. Babaie F, Hosseinzadeh R, Ebrazeh M, Seyfizadeh N, Aslani S, Salimi S, et al. The roles of ERAP1 and ERAP2 in autoimmunity and cancer immunity: New insights and perspective. Mol Immunol. 2020;121:7-19.
7. Afshar B, Khalifehzadeh-Esfahani Z, Seyfizadeh N, Rezaei Danbaran G, Hemmatzadeh M, Mohammadi H. The role of immune regulatory molecules in multiple sclerosis. J Neuroimmunol. 2019;337:577061.
8. Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent antitumor immunity. Nat Immunol. 2018;19(7):723-32.
9. Patsoukis N, Wang Q, Strauss L, Boussiotis VA. Revisiting the PD-1 pathway. Sci Advances. 2020;6(38):eabd2712.
10. Beldi-Ferchiou A, Caillat-Zucman S. Control of NK cell activation by immune checkpoint molecules. Int J Mol Sciences. 2017;18(10):2129.
11. Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, et al. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization. J Allergy Clin Immunol. 2017;139(1):335-46. e3.
12. Alvarez M, Simonetta F, Baker J, Morrison AR, Wenokur AS, Pierini A, et al. Indirect impact of PD-1/PD-L1 blockade on a murine model of NK cell exhaustion. Front Immunol. 2020:7.
13. Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze‐Koops H, et al. Role of Th17 cells in human autoimmune arthritis. Arthritis & Rheumatism. 2010;62(10):2876-85.
14. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature. 2000;408(6812):600-5.
15. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123-32.
16. Shen Q, Beucler MJ, Ray SC, Rappleye CA. Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens. PLoS Pathogens. 2018;14(11):e1007444.
17. Dalbeth N, Callan MF. A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2002;46(7):1763-72.
18. Romas E, Gillespie M, Martin T. Involvement of receptor activator of NFκB ligand and tumor necrosis factor-α in bone destruction in rheumatoid arthritis. Bone. 2002;30(2):340-6.
19. Hojjatipour T, Aslani S, Salimifard S, Mikaeili H, Hemmatzadeh M, Gholizadeh Navashenaq J, et al. NK cells - Dr. Jekyll and Mr. Hyde in autoimmune rheumatic diseases. Int Immunopharmacol. 2022;107:108682.
20. Shomali N, Suliman Maashi M, Baradaran B, Daei Sorkhabi A, Sarkesh A, Mohammadi H, et al. Dysregulation of survivin-targeting microRNAs in autoimmune diseases: new perspectives for novel therapies. Front Immunol. 2022:848.
21. Diener C, Keller A, Meese E. Emerging concepts of miRNA therapeutics: From cells to clinic. Trends in Genetics. 2022.
22. Swingler T, Niu L, Smith P, Paddy P, Le L, Barter M, et al. The function of microRNAs in cartilage and osteoarthritis. Clin Exp Rheumatol. 2019;37(5):40-7.
23. Saidi N, Ghalavand M, Hashemzadeh MS, Dorostkar R, Mohammadi H, Mahdian-Shakib A. Dynamic changes of epigenetic signatures during chondrogenic and adipogenic differentiation of mesenchymal stem cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2017;89:719-31.
24. Ebrahimiyan H, Rezaei N, Vojdanian M, Aslani S, Jamshidi A, Mahmoudi M. microRNA involvement in the regulation of survivin in peripheral blood mononuclear cells from rheumatoid arthritis patients. Int J Rheumatic Dis. 2019;22(6):1107-14.
25. Pesce S, Greppi M, Ferretti E, Obino V, Carlomagno S, Rutigliani M, et al. miRNAs in NK cell-based immune responses and cancer immunotherapy. Front Cell Develop Biol. 2020;8:119.
26. Li Q, Johnston N, Zheng X, Wang H, Zhang X, Gao D, et al. miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion. Oncotarget. 2016;7(33):53735.
27. Wei J, Nduom EK, Kong L-Y, Hashimoto Y, Xu S, Gabrusiewicz K, et al. MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. Neuro Oncol. 2016;18(5):639-48.
28. Zhang G, Li N, Li Z, Zhu Q, Li F, Yang C, et al. microRNA-4717 differentially interacts with its polymorphic target in the PD1 3′ untranslated region: A mechanism for regulating PD-1 expression and function in HBV-associated liver diseases. Oncotarget. 2015;6(22):18933.
29. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis & rheumatism. 2010;62(9):2569-81.
30. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8.
31. Yamin R, Berhani O, Peleg H, Aamar S, Stein N, Gamliel M, et al. High percentages and activity of synovial fluid NK cells present in patients with advanced stage active Rheumatoid Arthritis. Sci Reports. 2019;9(1):1-12.
32. Lin S-J, Hsu C-Y, Kuo M-L, Lee P-T, Hsiao H-S, Chen J-Y. Phenotypic and functional characterization of natural killer cells in rheumatoid arthritis-regulation with interleukin-15. Sci Reports. 2020;10(1):1-8.
33. Aramaki T, Ida H, Izumi Y, Fujikawa K, Huang M, Arima K, et al. A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis. Modern Rheumatol. 2009;19(3):245-52.
34. Richter J, Benson V, Grobarova V, Svoboda J, Vencovsky J, Svobodova R, et al. CD161 receptor participates in both impairing NK cell cytotoxicity and the response to glycans and vimentin in patients with rheumatoid arthritis. Clin Immunol. 2010;136(1):139-47.
35. Leavenworth JW, Wang X, Wenander CS, Spee P, Cantor H. Mobilization of natural killer cells inhibits development of collagen-induced arthritis. Proc Nat Academy Sci. 2011;108(35):14584-9.
36. Thanapati S, Ganu M, Giri P, Kulkarni S, Sharma M, Babar P, et al. Impaired NK cell functionality and increased TNF-α production as biomarkers of chronic chikungunya arthritis and rheumatoid arthritis. Hum Immunol. 2017;78(4):370-4.
37. Söderström K, Stein E, Colmenero P, Purath U, Müller-Ladner U, De Matos CT, et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Nat Acad Sci. 2010;107(29):13028-33.
38. De Matos CT, Berg L, Michaëlsson J, Felländer‐Tsai L, Kärre K, Söderström K. Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion. Immunology. 2007;122(2):291-301.
39. Nielsen N, Pascal V, Fasth AE, Sundström Y, Galsgaard ED, Ahern D, et al. Balance between activating NKG 2D, DNAM‐1, NK p44 and NK p46 and inhibitory CD 94/NKG 2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts. Immunology. 2014;142(4):581-93.
40. Chen J, Yang J, Qiao Y, Li X. Understanding the Regulatory Roles of Natural Killer T Cells in Rheumatoid Arthritis: T Helper Cell Differentiation Dependent or Independent? Scandinavian J Immunol. 2016;84(4):197-203.
41. Li Q, Johnston N, Zheng X, Wang H, Zhang X, Gao D, et al. miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion. Oncotarget. 2016;7(33):53735-50.
42. Zhang G, Li N, Li Z, Zhu Q, Li F, Yang C, et al. microRNA-4717 differentially interacts with its polymorphic target in the PD1 3' untranslated region: A mechanism for regulating PD-1 expression and function in HBV-associated liver diseases. Oncotarget. 2015;6(22):18933-44.
| Files | ||
| Issue | Vol 21 No 6 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i6.11524 | |
| Keywords | ||
| MicroRNA Natural killer cell NK cell exhaustion Programmed cell death protein 1 Rheumatoid arthritis | ||
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How to Cite
1.
Hemmatzadeh M, Ahangar Parvin E, Ghanavatinejad A, Rostami N, Hajaliloo M, Shomali N, Mohammadi H, Jadidi-Niaragh F. MicroRNAs Targeting Programmed Cell Death Protein 1 (PD-1) Promote Natural Killer Cell Exhaustion in Rheumatoid Arthritis. Iran J Allergy Asthma Immunol. 2022;21(6):646-656.
