Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis
Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis
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DOI：
10.4049/jimmunol.176.11.7021
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Radstake, TRDJ
中科院分区：
文献类型：
--
作者：
Roelofs, MF;Boelens, WC;Radstake, TRDJ
树突状细胞（Dendritic cells，DC）是一种特异性的APC，其可以在病原体识别以及内源性配体识别时被激活，所述内源性配体在炎症和细胞应激期间释放。类风湿关节炎（RA）患者滑膜组织中大量表达的TLR是识别外源性和内源性配体的关键。此外，发现TLR配体存在于RA血清和滑液中，并且与来自健康志愿者和患有系统性硬化症和系统性红斑狼疮的患者的血清和滑液相比显著增加。新的内源性TLR配体的鉴定可能有助于阐明TLR在RA和其他自身免疫性疾病中的作用。在这项研究中，我们研究了小热休克蛋白（HSP）家族的五个成员是否参与TLR 4介导的DC激活，以及这些小HSP是否存在于RA滑液组织中。在体外，用重组α A晶体蛋白、α B晶体蛋白、HSP 20、HSP B 8和HSP 27刺激单核细胞来源的DC。使用流式细胞术和多重细胞因子测定，我们表明aA晶体蛋白和HSPB8都能够激活DC，并且这种激活是TLR4依赖的。Western blot和免疫组化结果显示HSPB8在RA患者滑膜组织中呈高表达。通过这些实验，我们鉴定了sHSP aA晶体蛋白和HSPB8是两种新的内源性TLR 4配体，其中HSPB8在RA滑膜组织中大量表达。这些发现表明HSPB8在自身免疫性疾病如RA的炎症过程中发挥作用。
Dendritic cells (DCs) are specialized APCs that can be activated upon pathogen recognition as well as recognition of endogenous ligands, which are released during inflammation and cell stress. The recognition of exogenous and endogenous ligands depends on TLRs, which are abundantly expressed in synovial tissue from rheumatoid arthritis (RA) patients. Furthermore TLR ligands are found to be present in RA serum and synovial fluid and are significantly increased, compared with serum and synovial fluid from healthy volunteers and patients with systemic sclerosis and systemic lupus erythematosus. Identification of novel endogenous TLR ligands might contribute to the elucidation of the role of TLRs in RA and other autoimmune diseases. In this study, we investigated whether five members of the small heat shock protein (HSP) family were involved in TLR4-mediated DC activation and whether these small HSPs were present in RA synovial tissue. In vitro, monocyte-derived DCs were stimulated with recombinant alpha A crystallin, alpha B crystallin, HSP20, HSPB8, and HSP27. Using flow cytometry and multiplex cytokine assays, we showed that both aA crystallin and HSPB8 were able to activate DCs and that this activation was TLR4 dependent. Furthermore, Western blot and immunohistochemistry showed that HSPB8 was abundantly expressed in synovial tissue from patients with RA. With these experiments, we identified sHSP aA crystallin and HSPB8 as two new endogenous TLR4 ligands from which HSPB8 is abundantly expressed in RA synovial tissue. These findings suggest a role for HSPB8 during the inflammatory process in autoimmune diseases such as RA.