髓系相关蛋白 8 和 14 有助于尿酸单钠盐一水合物晶体诱导的痛风炎症。

Myeloid-related proteins 8 and 14 contribute to monosodium urate monohydrate crystal-induced inflammation in gout.

机构信息

University Hospital Muenster and University Children's Hospital Muenster, Muenster, Germany.

出版信息

Arthritis Rheumatol. 2014 May;66(5):1327-39. doi: 10.1002/art.38369.

DOI:10.1002/art.38369

PMID:24470119

Abstract

OBJECTIVE

Monosodium urate monohydrate (MSU) crystal-induced interleukin-1β (IL-1β) secretion is a critical factor in the pathogenesis of gout. However, without costimulation by a proIL-1β-inducing factor, MSU crystals alone are insufficient to induce IL-1β secretion. The responsible costimulatory factors that act as a priming endogenous signal in vivo are not yet known. We undertook this study to analyze the costimulatory properties of myeloid-related protein 8 (MRP-8) and MRP-14 (endogenous Toll-like receptor 4 [TLR-4] agonists) in MSU crystal-induced IL-1β secretion and their relevance in gout.

METHODS

MRP-8/MRP-14 was measured in paired serum and synovial fluid samples by enzyme-linked immunosorbent assay (ELISA) and localized in synovial tissue from gout patients by immunohistochemistry. Serum levels were correlated with disease activity, and MSU crystal-induced release of MRPs from human phagocytes was measured. Costimulatory effects of MRP-8 and MRP-14 on MSU crystal-induced IL-1β secretion from phagocytes were analyzed in vitro by ELISA, Western blotting, and polymerase chain reaction. The impact of MRP was tested in vivo in a murine MSU crystal-induced peritonitis model.

RESULTS

MRP-8/MRP-14 levels were elevated in the synovium, tophi, and serum of patients with gout and correlated with disease activity. MRP-8/MRP-14 was released by MSU crystal-activated phagocytes and increased MSU crystal-induced IL-1β secretion in a TLR-4-dependent manner. Targeted deletion of MRP-14 in mice led to a moderately reduced response of MSU crystal-induced inflammation in vivo.

CONCLUSION

MRP-8 and MRP-14, which are highly expressed in gout, are enhancers of MSU crystal-induced IL-1β secretion in vitro and in vivo. These endogenous TLR-4 ligands released by activated phagocytes contribute to the maintenance of inflammation in gout.

摘要

目的

尿酸单钠一水合物（MSU）晶体诱导的白细胞介素-1β（IL-1β）分泌是痛风发病机制中的一个关键因素。然而，没有前 IL-1β诱导因子的成本刺激，单独的 MSU 晶体不足以诱导 IL-1β分泌。作为体内初始内源性信号的负责的成本刺激因子尚不清楚。我们进行这项研究是为了分析髓样相关蛋白 8（MRP-8）和 MRP-14（内源性 Toll 样受体 4 [TLR-4] 激动剂）在 MSU 晶体诱导的 IL-1β分泌中的成本刺激特性及其在痛风中的相关性。

方法

通过酶联免疫吸附试验（ELISA）测量配对的血清和滑液样本中的 MRP-8/MRP-14，并通过免疫组织化学在痛风患者的滑膜组织中定位。血清水平与疾病活动相关，并测量 MSU 晶体从人吞噬细胞中释放 MRP 的情况。通过 ELISA、Western blot 和聚合酶链反应分析 MRP-8 和 MRP-14 对吞噬细胞中 MSU 晶体诱导的 IL-1β 分泌的成本刺激作用。在 MSU 晶体诱导的小鼠腹膜炎模型中体内测试 MRP 的影响。