Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis.
Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis.
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DOI：
10.4049/jimmunol.1302998
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Shahrara S
中科院分区：
文献类型：
--
作者：
Kim SJ;Chen Z;Chamberlain ND;Essani AB;Volin MV;Amin MA;Volkov S;Gravallese EM;Arami S;Swedler W;Lane NE;Mehta A;Sweiss N;Shahrara S
目的是研究TLR5结扎在类风湿关节炎（RA）和实验性关节炎病理中的影响。研究TLR5结扎在RA和小鼠髓细胞趋化性或破骨细胞形成中的作用；此外，揭示TNF-α功能在TLR5介导的发病机制中的意义。接下来，在胶原诱导关节炎（CIA）和局部关节TLR5结扎模型中确定其体内作用机制。最后，为了评估TLR5在RA中的作用，我们对CIA小鼠进行了抗TLR5抗体治疗。我们发现，TLR5激动剂鞭毛蛋白可以通过髓系TLR5结扎直接促进单核细胞浸润和破骨细胞成熟，并通过RA和小鼠细胞产生TNF-α间接促进。这两种已确定的TLR5功能可通过TNF-α增强，因为与单独使用每种因素相比，抑制这两种途径可更强烈地损害RA滑液驱动的单核细胞迁移和破骨细胞分化。在临床前研究中，CIA中鞭毛蛋白治疗后和体内局部TLR5结扎可刺激髓系细胞归巢和破骨发育，这与TNF-α级联反应有关。相反，当TLR5功能被阻断时，CIA关节炎症和骨侵蚀得到缓解。我们发现TLR5和TNF-α通路是相互关联的，因为TNF-α是在RA髓细胞中由TLR5连接产生的，抗TNF-α治疗可以显著抑制RA单核细胞中TLR5的表达。我们的新发现表明，TLR5驱动的RA炎症和骨破坏有直接和间接的机制。
The aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation; in addition, to uncover the significance of TNF-α function in TLR5 mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, anti-TLR5 antibody therapy was employed in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-α production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-α, as inhibition of both pathways can more strongly impair RA synovial fluid driven monocyte migration and osteoclast differentiation compared to each factor alone. In preclinical studies, flagellin post onset treatment in CIA and local TLR5 ligation in vivo, provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-α cascade. Reversely, CIA joint inflammation and bone erosion is alleviated when TLR5 function is blockade. We found that TLR5 and TNF-α pathways are interconnected, as TNF-α is produced by TLR5 ligation in RA myeloid cells, and anti-TNF-α therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct as well as an indirect mechanism is involved in TLR5 driven RA inflammation and bone destruction.
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影响因子：
27.4
作者：
Chamberlain ND;Kim SJ;Vila OM;Volin MV;Volkov S;Pope RM;Arami S;Mandelin AM 2nd;Shahrara S
通讯作者：
Shahrara S
影响因子：
4.4
作者：
Itoh, K;Udagawa, N;Takahashi, N
通讯作者：
Takahashi, N
影响因子：
5.5
作者：
Ayala, JM;Goyal, S;Hanlon, WA
通讯作者：
Hanlon, WA
影响因子：
4.4
作者：
Kim, Kyoung-Woon;Cho, Mi-La;Kim, Ho-Youn
通讯作者：
Kim, Ho-Youn
影响因子：
8.8
作者：
Kauppila, J. H.;Mattila, A. E.;Karttunen, T. J.;Salo, T.
通讯作者：
Salo, T.