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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...

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Autores principales: Zhang, Weixin, Noller, Kathleen, Crane, Janet, Wan, Mei, Wu, Xiaojun, Cahan, Patrick, Cao, Xu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10299822/
https://www.ncbi.nlm.nih.gov/pubmed/37204303
http://dx.doi.org/10.7554/eLife.85553
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author Zhang, Weixin
Noller, Kathleen
Crane, Janet
Wan, Mei
Wu, Xiaojun
Cahan, Patrick
Cao, Xu
author_facet Zhang, Weixin
Noller, Kathleen
Crane, Janet
Wan, Mei
Wu, Xiaojun
Cahan, Patrick
Cao, Xu
author_sort Zhang, Weixin
collection PubMed
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.
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spelling pubmed-102998222023-06-28 RANK(+)TLR2(+) myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis Zhang, Weixin Noller, Kathleen Crane, Janet Wan, Mei Wu, Xiaojun Cahan, Patrick Cao, Xu eLife Medicine 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. eLife Sciences Publications, Ltd 2023-05-19 /pmc/articles/PMC10299822/ /pubmed/37204303 http://dx.doi.org/10.7554/eLife.85553 Text en © 2023, Zhang, Noller et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Medicine
Zhang, Weixin
Noller, Kathleen
Crane, Janet
Wan, Mei
Wu, Xiaojun
Cahan, Patrick
Cao, Xu
RANK(+)TLR2(+) myeloid subpopulation converts autoimmune to joint destruction in 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 Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10299822/
https://www.ncbi.nlm.nih.gov/pubmed/37204303
http://dx.doi.org/10.7554/eLife.85553
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