RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis
- Johns Hopkins University, United States
- 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
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RANK+TLR2+ Myeloid Subpopulation Converts Autoimmune to Joint Destruction in Rheumatoid ArthritisNCBI Gene Expression Omnibus, GSE221704.
Article and author information
Author details
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).
Reviewing Editor
- Di Chen, Chinese Academy of Sciences, China
Publication history
- Received: December 13, 2022
- Accepted: May 18, 2023
- Accepted Manuscript published: May 19, 2023 (version 1)
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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RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis
eLife 12:e85553.
https://doi.org/10.7554/eLife.85553
Further reading
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- Medicine
- Neuroscience
Background:
Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations.
Methods:
In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors.
Results:
Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis.
Conclusions:
Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant.
Funding:
Key Technological Projects of Guangdong Province grant 2018B030335001.
Clinical trial number:
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- Biochemistry and Chemical Biology
- Medicine
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