IL-1 Receptor Accessory Protein: A Potential Biomarker for Determination of Disease Activity in Rheumatoid Arthritis
-
Zeinab Baghernejadan
,
Nahid Kianmehr
,
Anousheh Haghighi
,
Mohammad-Ali Assarehzadegan
,
Ali-Akbar Delbandi
,
Fatemeh Afrashteh
,
Zahra Saleh
,
Milad Karimi
,
Reza Falak
,
Majid Khoshmirsafa
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by persistent synovitis and synovial hyperplasia. Although interleukin 1 (IL-1) signaling is an important inflammatory pathway in RA, the regulation of IL-1 receptor accessory protein (IL-1RAP) has not been comprehensively characterized.
This cross-sectional study evaluated IL-1RAP alterations in RA at the transcriptional and protein levels, including its membrane-bound and soluble forms. Thirty female RA patients were stratified according to disease activity into low, moderate, and high disease activity subgroups, and 15 healthy controls were included. Surface expression of membrane-bound IL-1RAP (mIL-1RAP) was assessed on peripheral blood leukocyte subsets, including CD4+ and CD8+ T cells, B cells, monocytes, and granulocytes. Plasma soluble IL-1RAP (sIL-1RAP) levels were measured, and relative mRNA expression of IL1RAP, IL1A, IL1B, IL1R1, IL1R2, and IL1RN was quantified in peripheral blood mononuclear cells (PBMCs).
mIL-1RAP expression was increased in several immune cell subsets, particularly in patients with high disease activity, and was positively associated with disease activity. In contrast, circulating sIL-1RAP levels were reduced and inversely associated with disease activity. IL1RAP, IL1B, and IL1RN transcripts were elevated, with the highest expression in patients with high disease activity. IL1R1 and IL1R2 expression remained unchanged, whereas IL1A upregulation was limited to high disease activity.
These findings suggest disease activity–dependent alterations in IL-1RAP–related pathways in RA. IL-1RAP may represent a candidate biomarker of disease activity, but larger longitudinal studies are needed to validate its diagnostic, monitoring, and therapeutic relevance.
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3. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023-38.
4. Di Matteo A, Bathon JM, Emery P. Rheumatoid arthritis. Lancet. 2023;402(10416):2019-33.
5. Hsieh PH, Wu O, Geue C, McIntosh E, McInnes IB, Siebert S. Economic burden of rheumatoid arthritis: a systematic review of literature in biologic era. Ann Rheum Dis. 2020;79(6):771-777.
6. Shapiro SC. Biomarkers in rheumatoid arthritis. Cureus. 2021;13(5):e15063.
7. Abdelhafiz D, Baker T, Glascow DA, Abdelhafiz A. Biomarkers for the diagnosis and treatment of rheumatoid arthritis: a systematic review. Postgrad Med. 2023;135(3):214-23.
8. Dinarello CA. The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol. 2019;15(10):612-32.
9. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-19.
10. Nygaard G, Firestein GS. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat Rev Rheumatol. 2020;16(6):316-33.
11. Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, et al. Efficacy and safety of the human anti-IL-1β monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study. BMC Musculoskelet Disord. 2011;12:153.
12. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46(3):614-24.
13. Wang K, Luo H, Liu L, Gao H, Song Y, Li D. Blockade of IL-1 family cytokines in the treatment of rheumatoid arthritis. Front Pharmacol. 2025;16:1577628. doi:10.3389/fphar.2025.1577628.
14. Xu Y, Wang JY, Zou Y, Ma XW, Meng T. Role of IL-1 family cytokines IL-36, IL-37, and IL-38 in osteoarthritis and rheumatoid arthritis: a comprehensive review. J Inflamm Res. 2024;17:4001-16.
15. Liu Q, Wang Y, Jiang Y, Ru Y, Zhao Q, Zhang Z, et al. Anti-IL1RAP antibodies for pan-inhibition of IL-1 family cytokine signaling in inflammatory diseases and oncology. bioRxiv. 2026.
16. Fields JK, Günther S, Sundberg EJ. Structural basis of IL-1 family cytokine signaling. Front Immunol. 2019;10:1412.
17. Boraschi D, Italiani P, Weil S, Martin MU. The family of the interleukin-1 receptors. Immunol Rev. 2018;281(1):197-232
18. Petrackova A, Horak P, Radvansky M, Skacelova M, Fillerova R, Kudelka M, et al. Cross-disease innate gene signature: emerging diversity and abundance in RA compared to SLE and SSc. J Immunol Res. 2019;2019:3575803.
19. Petrackova A, Horak P, Radvansky M, Fillerova R, Smotkova Kraiczova V, Kudelka M, et al. Revealed heterogeneity in rheumatoid arthritis based on multivariate innate signature analysis. Clin Exp Rheumatol. 2020;38(2):289-298
20. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580-1588.
21. Smith DE, Hanna R, Della F, Moore H, Chen H, Farese AM, et al. The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action. Immunity. 2003;18(1):87-96.
22. Smeets RL, Joosten LA, Arntz OJ, Bennink MB, Takahashi N, Carlsen H, et al. Soluble interleukin-1 receptor accessory protein ameliorates collagen-induced arthritis by a different mode of action from that of interleukin-1 receptor antagonist. Arthritis Rheum. 2005;52(7):2202-11.
23. Migliorini P, Italiani P, Pratesi F, Puxeddu I, Boraschi D. Cytokines and soluble receptors of the interleukin-1 family in Schnitzler syndrome. Scand J Rheumatol. 2019;48(3):235-238.
24. Bozaoglu K, Attard C, Kulkarni H, Cummings N, Diego VP, Carless MA, et al. Plasma levels of soluble interleukin 1 receptor accessory protein are reduced in obesity. J Clin Endocrinol Metab. 2014;99(9):3435-43.
25. Michaud N, Al-Akoum M, Akoum A. Blood soluble interleukin 1 receptor accessory protein levels are consistently low throughout the menstrual cycle of women with endometriosis. Reprod Biol Endocrinol. 2014;12:51
26. Italiani P, Manca ML, Angelotti F, Melillo D, Pratesi F, Puxeddu I, et al. IL-1 family cytokines and soluble receptors in systemic lupus erythematosus. Arthritis Res Ther. 2018;20(1):27. doi:10.1186/s13075-018-1525-z.
27. Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009;30(4):576-587.
28. Lipsky PE, Thompson PA, Rosenwasser LJ, Dinarello CA. The role of interleukin 1 in human B cell activation: inhibition of B cell proliferation and the generation of immunoglobulin-secreting cells by an antibody against human leukocytic pyrogen. J Immunol. 1983;130(6):2708-2714.
29. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20(7):928-42.
30. Rana AK, Li Y, Dang Q, Yang F. Monocytes in rheumatoid arthritis: circulating precursors of macrophages and osteoclasts and their heterogeneity and plasticity role in RA pathogenesis. Int Immunopharmacol. 2018;65:348-59.
31. Salnikova DI, Nikiforov NG, Postnov AY, Orekhov AN. Target role of monocytes as key cells of innate immunity in rheumatoid arthritis. Diseases. 2024;12(5):81.
32. Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10(10):593-601.
33. Deng Y, Li J, Wu R. Neutrophils in rheumatoid arthritis synovium: implications on disease activity and inflammation state. J Inflamm Res. 2025;18:4741-4753.
34. Mitchell K, Barreyro L, Todorova TI, Taylor SJ, Antony-Debré I, Narayanagari SR, et al. IL1RAP potentiates multiple oncogenic signaling pathways in AML. J Exp Med. 2018;215(6):1709-27.
35. De Boer B, Sheveleva S, Apelt K, Vellenga E, Mulder AB, Huls G, et al. The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis. Haematologica. 2021;106(12):3067-78.
36. Lindkvist M, Göthlin Eremo A, Paramel GV, Anisul Haque S, Rydberg Millrud C, Rattik S, et al. IL1RAP expression in human atherosclerosis: a target of novel antibodies to reduce vascular inflammation and adhesion. J Am Heart Assoc. 2025;14(10):e039557.
37. Edwards CK 3rd, Green JS, Volk HD, Schiff M, Kotzin BL, Mitsuya H, et al. Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone. Front Immunol. 2012;3:366
38. Grönberg C, Rattik S, Tran-Manh C, Zhou X, Rius Rigau A, Li YN, et al. Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis. 2024;83(9):1156-68.
2. Radu AF, Bungau SG. Management of rheumatoid arthritis: an overview. Cells. 2021;10(11):2857.
3. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023-38.
4. Di Matteo A, Bathon JM, Emery P. Rheumatoid arthritis. Lancet. 2023;402(10416):2019-33.
5. Hsieh PH, Wu O, Geue C, McIntosh E, McInnes IB, Siebert S. Economic burden of rheumatoid arthritis: a systematic review of literature in biologic era. Ann Rheum Dis. 2020;79(6):771-777.
6. Shapiro SC. Biomarkers in rheumatoid arthritis. Cureus. 2021;13(5):e15063.
7. Abdelhafiz D, Baker T, Glascow DA, Abdelhafiz A. Biomarkers for the diagnosis and treatment of rheumatoid arthritis: a systematic review. Postgrad Med. 2023;135(3):214-23.
8. Dinarello CA. The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol. 2019;15(10):612-32.
9. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-19.
10. Nygaard G, Firestein GS. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat Rev Rheumatol. 2020;16(6):316-33.
11. Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, et al. Efficacy and safety of the human anti-IL-1β monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study. BMC Musculoskelet Disord. 2011;12:153.
12. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46(3):614-24.
13. Wang K, Luo H, Liu L, Gao H, Song Y, Li D. Blockade of IL-1 family cytokines in the treatment of rheumatoid arthritis. Front Pharmacol. 2025;16:1577628. doi:10.3389/fphar.2025.1577628.
14. Xu Y, Wang JY, Zou Y, Ma XW, Meng T. Role of IL-1 family cytokines IL-36, IL-37, and IL-38 in osteoarthritis and rheumatoid arthritis: a comprehensive review. J Inflamm Res. 2024;17:4001-16.
15. Liu Q, Wang Y, Jiang Y, Ru Y, Zhao Q, Zhang Z, et al. Anti-IL1RAP antibodies for pan-inhibition of IL-1 family cytokine signaling in inflammatory diseases and oncology. bioRxiv. 2026.
16. Fields JK, Günther S, Sundberg EJ. Structural basis of IL-1 family cytokine signaling. Front Immunol. 2019;10:1412.
17. Boraschi D, Italiani P, Weil S, Martin MU. The family of the interleukin-1 receptors. Immunol Rev. 2018;281(1):197-232
18. Petrackova A, Horak P, Radvansky M, Skacelova M, Fillerova R, Kudelka M, et al. Cross-disease innate gene signature: emerging diversity and abundance in RA compared to SLE and SSc. J Immunol Res. 2019;2019:3575803.
19. Petrackova A, Horak P, Radvansky M, Fillerova R, Smotkova Kraiczova V, Kudelka M, et al. Revealed heterogeneity in rheumatoid arthritis based on multivariate innate signature analysis. Clin Exp Rheumatol. 2020;38(2):289-298
20. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580-1588.
21. Smith DE, Hanna R, Della F, Moore H, Chen H, Farese AM, et al. The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action. Immunity. 2003;18(1):87-96.
22. Smeets RL, Joosten LA, Arntz OJ, Bennink MB, Takahashi N, Carlsen H, et al. Soluble interleukin-1 receptor accessory protein ameliorates collagen-induced arthritis by a different mode of action from that of interleukin-1 receptor antagonist. Arthritis Rheum. 2005;52(7):2202-11.
23. Migliorini P, Italiani P, Pratesi F, Puxeddu I, Boraschi D. Cytokines and soluble receptors of the interleukin-1 family in Schnitzler syndrome. Scand J Rheumatol. 2019;48(3):235-238.
24. Bozaoglu K, Attard C, Kulkarni H, Cummings N, Diego VP, Carless MA, et al. Plasma levels of soluble interleukin 1 receptor accessory protein are reduced in obesity. J Clin Endocrinol Metab. 2014;99(9):3435-43.
25. Michaud N, Al-Akoum M, Akoum A. Blood soluble interleukin 1 receptor accessory protein levels are consistently low throughout the menstrual cycle of women with endometriosis. Reprod Biol Endocrinol. 2014;12:51
26. Italiani P, Manca ML, Angelotti F, Melillo D, Pratesi F, Puxeddu I, et al. IL-1 family cytokines and soluble receptors in systemic lupus erythematosus. Arthritis Res Ther. 2018;20(1):27. doi:10.1186/s13075-018-1525-z.
27. Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009;30(4):576-587.
28. Lipsky PE, Thompson PA, Rosenwasser LJ, Dinarello CA. The role of interleukin 1 in human B cell activation: inhibition of B cell proliferation and the generation of immunoglobulin-secreting cells by an antibody against human leukocytic pyrogen. J Immunol. 1983;130(6):2708-2714.
29. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20(7):928-42.
30. Rana AK, Li Y, Dang Q, Yang F. Monocytes in rheumatoid arthritis: circulating precursors of macrophages and osteoclasts and their heterogeneity and plasticity role in RA pathogenesis. Int Immunopharmacol. 2018;65:348-59.
31. Salnikova DI, Nikiforov NG, Postnov AY, Orekhov AN. Target role of monocytes as key cells of innate immunity in rheumatoid arthritis. Diseases. 2024;12(5):81.
32. Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10(10):593-601.
33. Deng Y, Li J, Wu R. Neutrophils in rheumatoid arthritis synovium: implications on disease activity and inflammation state. J Inflamm Res. 2025;18:4741-4753.
34. Mitchell K, Barreyro L, Todorova TI, Taylor SJ, Antony-Debré I, Narayanagari SR, et al. IL1RAP potentiates multiple oncogenic signaling pathways in AML. J Exp Med. 2018;215(6):1709-27.
35. De Boer B, Sheveleva S, Apelt K, Vellenga E, Mulder AB, Huls G, et al. The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis. Haematologica. 2021;106(12):3067-78.
36. Lindkvist M, Göthlin Eremo A, Paramel GV, Anisul Haque S, Rydberg Millrud C, Rattik S, et al. IL1RAP expression in human atherosclerosis: a target of novel antibodies to reduce vascular inflammation and adhesion. J Am Heart Assoc. 2025;14(10):e039557.
37. Edwards CK 3rd, Green JS, Volk HD, Schiff M, Kotzin BL, Mitsuya H, et al. Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone. Front Immunol. 2012;3:366
38. Grönberg C, Rattik S, Tran-Manh C, Zhou X, Rius Rigau A, Li YN, et al. Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis. 2024;83(9):1156-68.
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How to Cite
1.
Baghernejadan Z, Kianmehr N, Haghighi A, Assarehzadegan M-A, Delbandi A-A, Afrashteh F, Saleh Z, Karimi M, Falak R, Khoshmirsafa M. IL-1 Receptor Accessory Protein: A Potential Biomarker for Determination of Disease Activity in Rheumatoid Arthritis. Iran J Allergy Asthma Immunol. 2026;:1-16.
