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

Abstract
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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

(2022) RANK+TLR2+ Myeloid Subpopulation Converts Autoimmune to Joint Destruction in Rheumatoid Arthritis
NCBI Gene Expression Omnibus, GSE221704.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE221704

Article and author information

Author details

Weixin Zhang

Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Kathleen Noller

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Janet Crane

Department of Orthopedic Surgery, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Mei Wan

Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States

Competing interests
Mei Wan, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-9404-540X
Xiaojun Wu

Department of Pathology, Johns Hopkins Medical Institutions, Washington, United States

Competing interests
No competing interests declared.
Patrick Cahan

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States

For correspondence
patrick.cahan@jhmi.edu

Competing interests
No competing interests declared.
Xu Cao

Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States

For correspondence
xcao11@jhmi.edu

Competing interests
No competing interests declared.

"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.

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).

Copyright

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.