RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis
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.
Sequencing data have been deposited in GEO under accession codes GSE221704
RANK+TLR2+ Myeloid Subpopulation Converts Autoimmune to Joint Destruction in Rheumatoid ArthritisNCBI Gene Expression Omnibus, GSE221704.
Article and author information
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.
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).
- Di Chen, Chinese Academy of Sciences, China
- Received: December 13, 2022
- Accepted: May 18, 2023
- Accepted Manuscript published: May 19, 2023 (version 1)
© 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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Key Technological Projects of Guangdong Province grant 2018B030335001.
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