RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis

  1. Weixin Zhang
  2. Kathleen Noller
  3. Janet Crane
  4. Mei Wan
  5. Xiaojun Wu
  6. Patrick Cahan  Is a corresponding author
  7. Xu Cao  Is a corresponding author
  1. Johns Hopkins University, United States
  2. Johns Hopkins Medical Institutions, United States

Abstract

Joint destruction is the major clinic burden in patients with rheumatoid arthritis (RA). It is unclear, though, how this autoimmune disease progresses to the point of deterioration of the joint. Here, we report that in a mouse model of RA the upregulation of TLR2 expression and its a(2,3) sialylation in RANK+ myeloid monocytes mediate the transition from autoimmunity to osteoclast fusion and bone resorption, resulting in joint destruction. The expression of a(2,3) sialyltransferases were significantly increased in RANK+TLR2+ myeloid monocytes, and their inhibition or treatment with a TLR2 inhibitor blocked osteoclast fusion. Notably, analysis of our single-cell RNA-sequencing (scRNA-seq) libraries generated from RA mice revealed a novel RANK+TLR2- subset that negatively regulated osteoclast fusion. Importantly, the RANK+TLR2+ subset was significantly diminished with the treatments, whereas the RANK+TLR2- subset was expanded. Moreover, the RANK+TLR2- subset could differentiate into a TRAP+ osteoclast lineage, but the resulting cells did not fuse to form osteoclasts. Our scRNA-seq data showed that Maf is highly expressed in the RANK+TLR2- subset, and the a(2,3) sialyltransferase inhibitor induced Maf expression in the RANK+TLR2+ subset. The identification of a RANK+TLR2- subset provides a potential explanation for TRAP+ mononuclear cells in bone and their anabolic activity. Further, TLR2 expression and its a(2,3) sialylation in the RANK+ myeloid monocytes could be effective targets to prevent autoimmune-mediated joint destruction.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE221704

The following data sets were generated

Article and author information

Author details

  1. Weixin Zhang

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  2. Kathleen Noller

    Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Janet Crane

    Department of Orthopedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Mei Wan

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    Mei Wan, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9404-540X
  5. Xiaojun Wu

    Department of Pathology, Johns Hopkins Medical Institutions, Washington, United States
    Competing interests
    No competing interests declared.
  6. Patrick Cahan

    Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States
    For correspondence
    patrick.cahan@jhmi.edu
    Competing interests
    No competing interests declared.
  7. Xu Cao

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    For correspondence
    xcao11@jhmi.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8614-6059

Funding

National Institute on Aging (R01 AG076783)

  • Xu Cao

National Institute on Aging (R01 AG068997)

  • Xu Cao

National Institute on Aging (P01 AG066603)

  • Xu Cao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Di Chen, Chinese Academy of Sciences, China

Ethics

Animal experimentation: All animals were kept in the Animal Facility of the Johns Hopkins University School of Medicine. The animal protocol was approved by the Institutional Animal Care and Use Committee of Johns Hopkins University, Baltimore, MD, USA (MO21M276).

Version history

  1. Received: December 13, 2022
  2. Accepted: May 18, 2023
  3. Accepted Manuscript published: May 19, 2023 (version 1)
  4. Version of Record published: June 27, 2023 (version 2)
  5. Version of Record updated: July 11, 2023 (version 3)

Copyright

© 2023, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Weixin Zhang
  2. Kathleen Noller
  3. Janet Crane
  4. Mei Wan
  5. Xiaojun Wu
  6. Patrick Cahan
  7. Xu Cao
(2023)
RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis
eLife 12:e85553.
https://doi.org/10.7554/eLife.85553

Share this article

https://doi.org/10.7554/eLife.85553

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