TY - JOUR TI - RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis AU - Zhang, Weixin AU - Noller, Kathleen AU - Crane, Janet AU - Wan, Mei AU - Wu, Xiaojun AU - Cahan, Patrick AU - Cao, Xu A2 - Chen, Di A2 - Zaidi, Mone A2 - Wang, Ting-Yu VL - 12 PY - 2023 DA - 2023/05/19 SP - e85553 C1 - eLife 2023;12:e85553 DO - 10.7554/eLife.85553 UR - https://doi.org/10.7554/eLife.85553 AB - 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. KW - toll-like receptor 2 KW - sialylation KW - osteoclast KW - fusion KW - rheumatoid arthritis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -