Extracellular microRNAs induce dendritic cell-dependent joint inflammation and potentiate osteoclast differentiation via TLR7/8 engagement

TLR7型 细胞生物学 破骨细胞 炎症 化学 树突状细胞 兰克尔 免疫系统 癌症研究 生物 激活剂(遗传学) 免疫学 Toll样受体 受体 生物化学 先天免疫系统
作者
Carolina Gaudenzi,Tiziana Schioppa,Mauro Passari,Giovanni Zucchi,Laura Tiberio,Yasmin Vahidi,Sara Scutera,Tiziana Musso,Silvano Sozzani,Annalisa Del Prete,Valentina Salvi,Daniela Bosisio
出处
期刊:Journal of Autoimmunity [Elsevier]
卷期号:145: 103189-103189
标识
DOI:10.1016/j.jaut.2024.103189
摘要

Monocyte-derived dendritic cells (DCs) are key players in the induction of inflammation, autoreactive T cell activation and loss of tolerance in rheumatoid arthritis (RA), but the precise mechanisms underlying their activation remain elusive. Here, we hypothesized that extracellular microRNAs released in RA synovial fluids may represent a novel, physiological stimulus triggering unwanted immune response via TLR8-expressing DC stimulation. Human monocyte-derived DCs were stimulated with a mixture of GU-rich miRNAs upregulated in RA tissues and released in synovial fluids (Ex-miRNAs). Activation of DCs was assessed in terms of NF-κB activation by Western blot, cytokine production by ELISA, T cell proliferation and polarization by allogeneic mixed lymphocyte reaction. DC differentiation into osteoclasts was evaluated in terms of tartrate-resistant acid phosphatase production and formation of resorption pits in dentine slices. Induction of joint inflammation in vivo was evaluated using a murine model of DC-induced arthritis. TLR7/8 involvement was assessed by specific inhibitors. Ex-miRNAs activate DCs to secrete TNFα, induce joint inflammation, start an early autoimmune response and potentiate the differentiation of DCs into aggressive osteoclasts. This work represents a proof of concept that the pool of extracellular miRNAs overexpressed in RA joints can act as a physiological activator of inflammation via the stimulation of TLR8 expressed by human DCs, which in turn exert arthritogenic functions. In this scenario, pharmacological inhibition of TLR8 might offer a new therapeutic option to reduce inflammation and osteoclast-mediated bone destruction in RA.
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