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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. 2020;18(9):2199-2210doi: 10.1038/s41423-020-0433-8.
Umar, S., Palasiewicz, K., Van Raemdonck, K., Volin, M. V., Romay, B., Amin, M. A., Zomorrodi, R. K., Arami, S., Gonzalez, M., Rao, V., Zanotti, B., Fox, D. A., Sweiss, N., & Shahrara, S. (2021). IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion. Cellular & molecular immunology, 18(9), 2199-2210. https://doi.org/10.1038/s41423-020-0433-8
Umar, Sadiq, et al. "IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion." Cellular & molecular immunology vol. 18,9 (2021): 2199-2210. doi: https://doi.org/10.1038/s41423-020-0433-8
Umar S, Palasiewicz K, Van Raemdonck K, Volin MV, Romay B, Amin MA, Zomorrodi RK, Arami S, Gonzalez M, Rao V, Zanotti B, Fox DA, Sweiss N, Shahrara S. IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion. Cell Mol Immunol. 2021 Sep;18(9):2199-2210. doi: 10.1038/s41423-020-0433-8. Epub 2020 May 15. PMID: 32415262; PMCID: PMC8429735.
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Cell Mol Immunol. 2021 Sep;18(9):2199-2210. doi: 10.1038/s41423-020-0433-8. Epub 2020 May 15.

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

Cellular & molecular immunology

Sadiq Umar, Karol Palasiewicz, Katrien Van Raemdonck, Michael V Volin, Bianca Romay, M Asif Amin, Ryan K Zomorrodi, Shiva Arami, Mark Gonzalez, Vikram Rao, Brian Zanotti, David A Fox, Nadera Sweiss, Shiva Shahrara

Affiliations

  1. Jesse Brown VA Medical Center, Chicago, IL, 60612, USA.
  2. Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  3. Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL, 60515, USA.
  4. Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, 481096, USA.
  5. Department of Orthopedic Surgery, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  6. Pfizer Research, Cambridge, MA, 02139, USA.
  7. Jesse Brown VA Medical Center, Chicago, IL, 60612, USA. [email protected].
  8. Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA. [email protected].

PMID: 32415262 PMCID: PMC8429735 DOI: 10.1038/s41423-020-0433-8

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

© 2020. CSI and USTC.

Keywords: IRAK4; MΦs; RA FLSs; T cells; TLR7; osteoclasts

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