Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling.
Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling.
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DOI：
10.4049/jimmunol.0801563
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发表时间：
2009-04-15
期刊：
影响因子：
--
通讯作者：
Pope RM
中科院分区：
文献类型：
--
作者：
Huang QQ;Sobkoviak R;Jockheck-Clark AR;Shi B;Mandelin AM 2nd;Tak PP;Haines GK 3rd;Nicchitta CV;Pope RM
巨噬细胞是慢性炎症的重要介质，在类风湿关节炎(RA)患者的滑膜衬里和滑膜下层中占有重要地位。最近，我们发现类风湿关节炎关节巨噬细胞中Toll样受体(TLR)2和4的表达增加，并且对微生物TLR2和TLR4配体的反应增强。本研究研究了96 kDa热休克糖蛋白(Gp96)在RA关节中的表达及其作为内源性TLR配体在促进RA天然免疫中的作用。与骨性关节炎和非关节炎对照滑膜组织相比，类风湿性关节炎患者的滑膜组织中gp96表达升高。Gp96的表达与炎症和滑膜衬里厚度密切相关。类风湿关节炎关节滑液中gp96含量较疾病对照组升高。重组gp96是一种有效的巨噬细胞激活剂，其激活主要通过TLR2信号途径实现。与RA或健康对照组的外周血单核细胞相比，RA滑膜巨噬细胞对gp96的细胞反应显著增强。Gp96可显著诱导RA滑膜巨噬细胞表达TLR2、肿瘤坏死因子α和IL-8，但不能诱导TLR4的转录，且对纯化的RA滑膜巨噬细胞的诱导作用更强。滑液巨噬细胞表达TLR2，但不表达TLR4，与滑液中gp96水平密切相关。本研究记录了gp96作为内源性TLR2配体在RA中的潜在作用，并对gp96促进RA慢性炎症的机制提供了洞察力，将gp96确定为潜在的新的治疗靶点。
Macrophages are important mediators of chronic inflammation and are prominent in the synovial lining and sublining of patients with rheumatoid arthritis (RA). Recently, we demonstrated increased toll like receptor (TLR) 2 and 4 expression and increased response to microbial TLR2 and TLR4 ligands in macrophages from the joints of RA. The current study characterized the expression of the 96-kDa heat shock glycoprotein (gp96) in the joints of RA and its role as an endogenous TLR ligand to promote innate immunity in RA. Gp96 was increased in RA compared with osteoarthritis and arthritis-free control synovial tissues. The expression of gp96 strongly correlated with inflammation and synovial lining thickness. Gp96 was increased in synovial fluid from the joints of RA compared with disease controls. Recombinant gp96 was a potent activator of macrophages, and the activation was mediated primarily through TLR2 signaling. The cellular response to gp96 was significantly stronger with RA synovial macrophages compared to peripheral blood monocytes from RA or healthy controls. The transcription of TLR2, TNFα and IL-8, but not TLR4, was significantly induced by gp96, and the induction was significantly greater in purified RA synovial macrophages. The expression of TLR2, but not TLR4, on synovial fluid macrophages strongly correlated with the level of gp96 in the synovial fluid. The present study documents the potential role of gp96 as an endogenous TLR2 ligand in RA and provides insight into the mechanism by which gp96 promotes the chronic inflammation of RA, identifying gp96 as a potential new therapeutic target.
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影响因子：
15.9
作者：
Abdollahi-Roodsaz, Shahla;Joosten, Leo A. B.;Van den Berg, Wim B.
通讯作者：
Van den Berg, Wim B.
影响因子：
4.8
作者：
Asea, A;Rehli, M;Calderwood, SK
通讯作者：
Calderwood, SK
影响因子：
5.3
作者：
Pagliari, LJ;Perlman, H;Pope, RM
通讯作者：
Pope, RM
影响因子：
20.3
作者：
Hilf, N;Singh-Jasuja, H;Schild, H
通讯作者：
Schild, H
影响因子：
4.4
作者：
Liu, HT;Eksarko, P;Pope, RM
通讯作者：
Pope, RM