Expression and function of the NALP3 inflammasome in rheumatoid synovium
Expression and function of the NALP3 inflammasome in rheumatoid synovium
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DOI：
10.1111/j.1365-2567.2009.03174.x
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发表时间：
2010-02-01
期刊：
影响因子：
6.4
通讯作者：
So, Alexander
中科院分区：
文献类型：
--
作者：
Kolly, Laeticia;Busso, Nathalie;So, Alexander
P&gT；含有Nacht、LRR和PYD结构域的蛋白(NALP3)炎症小体是白细胞介素1β(IL-1β)分泌的关键调节因子。由于有强有力的证据表明IL-1β在类风湿关节炎(RA)和小鼠关节炎模型中具有促炎作用，我们研究了NALP3炎症体的不同成分以及其他核苷酸寡聚化结构域(NOD)样受体(NLRs)在RA患者滑膜中的表达。此外，还研究了NLRs在关节成纤维细胞系中的表达。免疫组织化学显示，NALP3和含卡片结构域的凋亡相关斑点样蛋白(ASC)在髓系细胞、内皮细胞和B细胞中均有表达。T细胞表达ASC，但缺乏NALP3。在滑膜成纤维细胞系中，未检测到NALP3在RNA和蛋白质水平的表达，已知的NALP3激动剂刺激未能诱导IL-1β的分泌。有趣的是，我们不能根据已知NLR蛋白的基本RNA表达水平来区分RA和骨性关节炎滑膜样本，尽管通过酶联免疫吸附试验检测RA样本中caspase-1的水平更高。这些结果表明，髓样细胞和内皮细胞是炎症小体介导的滑膜IL-1β产生的主要来源，滑膜成纤维细胞由于缺乏NALP3而无法激活caspase-1。NALP3炎症体活性不能解释类风湿关节炎和骨性关节炎之间炎症程度的差异。
P>The NACHT, LRR and PYD domains containing protein (NALP3) inflammasome is a key regulator of interleukin-1 beta (IL-1 beta) secretion. As there is strong evidence for a pro-inflammatory role of IL-1 beta in rheumatoid arthritis (RA) and in murine models of arthritis, we explored the expression of the different components of the NALP3 inflammasome as well as other nucleotide oligomerization domain (NOD)-like receptors (NLRs) in synovium obtained from patients with RA. The expression of NLRs was also studied in fibroblast lines derived from joint tissue. By immunohistology, NALP3 and apoptosis-associated speck-like protein containing a CARD domain (ASC) were expressed in myeloid and endothelial cells and B cells. T cells expressed ASC but lacked NALP3. In synovial fibroblast lines, NALP3 expression was not detected at the RNA and protein levels and stimulation with known NALP3 agonists failed to induce IL-1 beta secretion. Interestingly, we were unable to distinguish RA from osteoarthritis synovial samples on the basis of their basal level of RNA expression of known NLR proteins, though RA samples contained higher levels of caspase-1 assayed by enzyme-linked immunsorbent assay. These results indicate that myeloid and endothelial cells are the principal sources of inflammasome-mediated IL-1 beta production in the synovium, and that synovial fibroblasts are unable to activate caspase-1 because they lack NALP3. The NALP3 inflammasome activity does not account for the difference in level of inflammation between RA and osteoarthritis.