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

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.

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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.

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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.

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Correspondence to Shiva Shahrara.

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

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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

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Keywords

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

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