Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion

Cellular & Molecular Immunology volume 18, pages 2199–2210 (2021)Cite this article

Subjects

Abstract

Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis (RA) patients could reflect activation of innate immune mechanisms. Herein, we show that a TLR7 GU-rich endogenous ligand, miR-Let7b, potentiates synovitis by amplifying RA monocyte and fibroblast (FLS) trafficking. miR-Let7b ligation to TLR7 in macrophages (MΦs) and FLSs expanded the synovial inflammatory response. Moreover, secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell differentiation. We showed that IRAK4 inhibitor (i) therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦ or FLS activation, as well as monokine-modulated Th1/Th17 cell polarization. IRAK4i therapy also disrupted RA osteoclastogenesis, which was amplified by miR-Let7b ligation to joint myeloid TLR7. Hence, the effectiveness of IRAK4i was compared with that of a TNF inhibitor (i) or anti-IL-6R treatment in collagen-induced arthritis (CIA) and miR-Let7b-mediated arthritis. We found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480+iNOS+ MΦs, the expression of certain monokines, and Th1 cell differentiation. Unexpectedly, these biologic therapies were unable to alleviate miR-Let7b-induced arthritis. The superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480+iNOS+ MΦs, vimentin+ fibroblasts, and CD3+ T cells, in addition to negating the expression of a wide range of monokines, including IL-12, MIP2, and IRF5 and Th1/Th17 lymphokines. In conclusion, IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Elshabrawy, H. A., Essani, A. E., Szekanecz, Z., Fox, D. A. & Shahrara, S. TLRs, future potential therapeutic targets for RA. Autoimmun. Rev. 16, 103–113 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Chamberlain, N. D. et al. Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFalpha in monocytes. Ann. Rheum. Dis. 72, 418–426 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Kim, S. J. et al. Identification of a novel toll-like receptor 7 endogenous ligand in rheumatoid arthritis synovial fluid that can provoke arthritic joint inflammation. Arthritis Rheumatol. 68, 1099–1110 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Negishi, H. et al. Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis. Proc. Natl Acad. Sci. USA 116, 23653–23661 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Salvi, V., et al. Exosome-delivered microRNAs promote IFN-alpha secretion by human plasmacytoid DCs via TLR7. JCI Insight. 3 (2018).

  6. Li, Q. et al. MicroRNA-574-5p was pivotal for TLR9 signaling enhanced tumor progression via down-regulating checkpoint suppressor 1 in human lung cancer. PLoS ONE 7, e48278 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alzabin, S. et al. Investigation of the role of endosomal Toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance. Arthritis Res Ther. 14, R142 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen, S. Y. et al. Suppression of collagen-induced arthritis by intra-articular lentiviral vector-mediated delivery of Toll-like receptor 7 short hairpin RNA gene. Gene Ther. 19, 752–760 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Dayer, J. M., Oliviero, F. & Punzi, L. A brief history of IL-1 and IL-1 Ra in rheumatology. Front. Pharmacol. 8, 293 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Koziczak-Holbro, M. et al. IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression. J. Biol. Chem. 282, 13552–13560 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Cushing, L. et al. IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes. J. Biol. Chem. 292, 18689–18698 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhu, W. et al. Anti-citrullinated protein antibodies induce macrophage subset disequilibrium in RA patients. Inflammation. 38, 2067–2075 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Krausgruber, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol. 12, 231–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Weiss, M. et al. IRF5 controls both acute and chronic inflammation. Proc. Natl Acad. Sci. USA 112, 11001–11006 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Duffau, P. et al. Promotion of inflammatory arthritis by interferon regulatory factor 5 in a mouse model. Arthritis Rheumatol. 67, 3146–3157 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim, T. W. et al. A critical role for IRAK4 kinase activity in toll-like receptor-mediated innate immunity. J. Exp. Med 204, 1025–1036 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Genung, N. E. & Guckian, K. M. Small molecule inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4). Prog. Med. Chem. 56, 117–163 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Hasham, M. G. et al. Systemic autoimmunity induced by the TLR7/8 agonist Resiquimod causes myocarditis and dilated cardiomyopathy in a new mouse model of autoimmune heart disease. Dis. Model Mech. 10, 259–270 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kawai, T. et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5, 1061–1068 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Spinetti, T. et al. TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function. Oncoimmunology 5, e1230578 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Kim, H. et al. Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy. Biomaterials 164, 38–53 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Cho, J. H. et al. The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti-tumoral and systemic immunity during radiotherapy for melanoma. Oncotarget 8, 24932–24948 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xiao, Q. et al. TLR7 engagement on dendritic cells enhances autoreactive Th17 responses via activation of ERK. J. Immunol. 197, 3820–3830 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Ye, J. et al. TLR7 signaling regulates Th17 cells and autoimmunity: novel potential for autoimmune therapy. J. Immunol. 199, 941–954 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Miyamoto, A. et al. R848, a toll-like receptor 7 agonist, inhibits osteoclast differentiation but not survival or bone-resorbing function of mature osteoclasts. Cytotechnology 64, 331–339 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ye, X. J. et al. The roles of interleukin-18 in collagen-induced arthritis in the BB rat. Clin. Exp. Immunol. 136, 440–447 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alzabin, S. et al. Incomplete response of inflammatory arthritis to TNFalpha blockade is associated with the Th17 pathway. Ann. Rheum. Dis. 71, 1741–1748 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Fujimoto, M. et al. Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum. 58, 3710–3719 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Notley, C. A. et al. Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J. Exp. Med 205, 2491–2497 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Thiolat, A. et al. Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheumatol. 66, 273–283 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Depis, F. et al. Long-term amelioration of established collagen-induced arthritis achieved with short-term therapy combining anti-CD3 and anti-tumor necrosis factor treatments. Arthritis Rheum. 64, 3189–3198 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Kitaura, H. et al. M-CSF mediates TNF-induced inflammatory osteolysis. J. Clin. Invest 115, 3418–3427 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wong, P. K. et al. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum. 54, 158–168 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Zhu, F. G. et al. A novel antagonist of Toll-like receptors 7, 8 and 9 suppresses lupus disease-associated parameters in NZBW/F1 mice. Autoimmunity 46, 419–428 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Balak, D. M. et al. IMO-8400, a toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis. Clin. Immunol. 174, 63–72 (2017).

    Article  CAS  PubMed  Google Scholar 

  36. Suarez-Farinas, M. et al. Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation. PLoS ONE 8, e84634 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Gimenez, N. et al. Targeting IRAK4 disrupts inflammatory pathways and delays tumor development in chronic lymphocytic leukemia. Leukemia 34, 100–114 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. Arnett, F. C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

    Article  CAS  PubMed  Google Scholar 

  39. Chen, Z. et al. The novel role of IL-7 ligation to IL-7 receptor in myeloid cells of rheumatoid arthritis and collagen-induced arthritis. J. Immunol. 190, 5256–5266 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Chen, Z. et al. Characterising the expression and function of CCL28 and its corresponding receptor, CCR10, in RA pathogenesis. Ann. Rheum. Dis. 74, 1898–1906 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Kim, S. J. et al. Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis. J. Immunol. 193, 3902–3913 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Kim, S. J. et al. Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status. Ann. Rheum. Dis. 76, 731–739 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Kim, S. J., et al. Macrophages are the primary effector cells in IL-7-induced arthritis. Cell Mol Immunol. https://doi.org/10.1038/s41423-019-0235-z (2019).

  44. Van Raemdonck, K., et al. CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis. Cell Mol Life Sci. 77, 1387–1399 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Pickens, S. R. et al. Characterization of CCL19 and CCL21 in rheumatoid arthritis. Arthritis Rheum. 63, 914–922 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pickens, S. R. et al. Characterization of interleukin-7 and interleukin-7 receptor in the pathogenesis of rheumatoid arthritis. Arthritis Rheum. 63, 2884–2893 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chamberlain, N. D. et al. TLR5, a novel and unidentified inflammatory mediator in rheumatoid arthritis that correlates with disease activity score and joint TNF-alpha levels. J. Immunol. 189, 475–483 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Elshabrawy, H. A. et al. IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells. Angiogenesis 21, 215–228 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lee, K. L. et al. Discovery of clinical candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-06650833), a potent, selective inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4), by fragment-based drug design. J. Med. Chem. 60, 5521–5542 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Danto, S. I. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects. Arthritis Res Ther. 21, 269 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Morgan, R. et al. Expression and function of aminopeptidase N/CD13 produced by fibroblast-like synoviocytes in rheumatoid arthritis: role of CD13 in chemotaxis of cytokine-activated T cells independent of enzymatic activity. Arthritis Rheumatol. 67, 74–85 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pickens, S. R. et al. Local expression of interleukin-27 ameliorates collagen-induced arthritis. Arthritis Rheum. 63, 2289–2298 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kim, S. J. et al. Angiogenesis in rheumatoid arthritis is fostered directly by toll-like receptor 5 ligation and indirectly through interleukin-17 induction. Arthritis Rheum. 65, 2024–2036 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cushing, L. et al. Interleukin 1/Toll-like receptor-induced autophosphorylation activates interleukin 1 receptor-associated kinase 4 and controls cytokine induction in a cell type-specific manner. J. Biol. Chem. 289, 10865–10875 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by awards from the Department of Veteran’s Affairs MERIT Award (1I01BX002286), the National Institutes of Health (AR056099 and AR065778), the National Psoriasis Foundation (NPF), the Pfizer Investigator Initiated Research (IIR) Program, and the Chicago Biomedical Consortium (CBC) Accelerator Award.

Author information

Authors and Affiliations

  1. Jesse Brown VA Medical Center, Chicago, IL, 60612, USA

    Sadiq Umar, Karol Palasiewicz, Katrien Van Raemdonck, Shiva Arami & Shiva Shahrara

  2. Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Sadiq Umar, Karol Palasiewicz, Katrien Van Raemdonck, Bianca Romay, Ryan K. Zomorrodi, Shiva Arami, Nadera Sweiss & Shiva Shahrara

  3. Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL, 60515, USA

    Michael V. Volin & Brian Zanotti

  4. Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, 481096, USA

    M. Asif Amin & David A. Fox

  5. Department of Orthopedic Surgery, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Mark Gonzalez

  6. Pfizer Research, Cambridge, MA, 02139, USA

    Vikram Rao

Authors
  1. Sadiq Umar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karol Palasiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katrien Van Raemdonck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael V. Volin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bianca Romay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Asif Amin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryan K. Zomorrodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shiva Arami
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mark Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vikram Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Brian Zanotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David A. Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nadera Sweiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shiva Shahrara
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors were involved in drafting the article or critically revising it for important intellectual content, and all authors approved the final version to be published. SS had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: SU and SS. Acquisition of data: SU, KP, MVV, BR, RKZ, BZ, and SS. Analysis and interpretation of data: SU, KP, KVR, MVV, MAA, BR, RKZ, DAF, BZ, and SS. Providing crucial reagents: SA, NS, MAA, VR, and MG.

Corresponding author

Correspondence to Shiva Shahrara.

Ethics declarations

Competing interests

The authors declare that they have no conflict of interest. VR is employed by Pfizer.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Umar, S., Palasiewicz, K., Van Raemdonck, K. et al. IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion. Cell Mol Immunol 18, 2199–2210 (2021). https://doi.org/10.1038/s41423-020-0433-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-0433-8

Keywords

  • TLR7
  • MΦs
  • RA FLSs
  • osteoclasts
  • T cells
  • IRAK4

This article is cited by

Search

Advanced search

Quick links