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 α(2,3) sialylatio...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/85553 |
| _version_ | 1797783058873581568 |
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| author | Weixin Zhang Kathleen Noller Janet Crane Mei Wan Xiaojun Wu Patrick Cahan Xu Cao |
| author_facet | Weixin Zhang Kathleen Noller Janet Crane Mei Wan Xiaojun Wu Patrick Cahan Xu Cao |
| author_sort | Weixin Zhang |
| collection | DOAJ |
| description | 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 α(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 α(2,3) sialyltransferases was 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− a 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 α(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 α(2,3) sialylation in the RANK+ myeloid monocytes could be effective targets to prevent autoimmune-mediated joint destruction. |
| first_indexed | 2024-03-13T00:19:45Z |
| format | Article |
| id | doaj.art-d0751e5977204ef6866406130af5893f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-13T00:19:45Z |
| publishDate | 2023-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d0751e5977204ef6866406130af5893f2023-07-11T16:37:15ZengeLife Sciences Publications LtdeLife2050-084X2023-05-011210.7554/eLife.85553RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritisWeixin Zhang0https://orcid.org/0000-0002-1009-101XKathleen Noller1https://orcid.org/0000-0001-7915-3269Janet Crane2Mei Wan3https://orcid.org/0000-0001-9404-540XXiaojun Wu4Patrick Cahan5Xu Cao6https://orcid.org/0000-0001-8614-6059Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States; Zhejiang Chinese Medical University, Hangzhou, ChinaDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, United StatesDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States; Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United StatesDepartment of Pathology, Johns Hopkins Medical Institutions, Washington, United StatesDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, United StatesDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United StatesJoint 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 α(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 α(2,3) sialyltransferases was 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− a 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 α(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 α(2,3) sialylation in the RANK+ myeloid monocytes could be effective targets to prevent autoimmune-mediated joint destruction.https://elifesciences.org/articles/85553toll-like receptor 2sialylationosteoclastfusionrheumatoid arthritis |
| spellingShingle | Weixin Zhang Kathleen Noller Janet Crane Mei Wan Xiaojun Wu Patrick Cahan Xu Cao RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis eLife toll-like receptor 2 sialylation osteoclast fusion rheumatoid arthritis |
| title | RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis |
| title_full | RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis |
| title_fullStr | RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis |
| title_full_unstemmed | RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis |
| title_short | RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis |
| title_sort | rank tlr2 myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis |
| topic | toll-like receptor 2 sialylation osteoclast fusion rheumatoid arthritis |
| url | https://elifesciences.org/articles/85553 |
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