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

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. Access through your institution Buy or subscribe This is a preview of subscription

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(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 * Jesse Brown VA Medical Center, Chicago, IL, 60612, USA Sadiq Umar, Karol Palasiewicz, 

Katrien Van Raemdonck, Shiva Arami & Shiva Shahrara * 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 * Department of Microbiology and Immunology, Midwestern University,

Downers Grove, IL, 60515, USA Michael V. Volin & Brian Zanotti * Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, 481096,

USA M. Asif Amin & David A. Fox * Department of Orthopedic Surgery, University of Illinois at Chicago, Chicago, IL, 60612, USA Mark Gonzalez * Pfizer Research, Cambridge, MA, 02139, USA

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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 SUPPLEMENTARY S1 RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE 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: 13 January 2020 * Accepted: 30 March 2020 *

Published: 15 May 2020 * Issue Date: September 2021 * DOI: https://doi.org/10.1038/s41423-020-0433-8 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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KEYWORDS * TLR7 * MΦs * RA FLSs * osteoclasts * T cells * IRAK4