Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation.
Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation.
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基于Gadolinium的化合物诱导NLRP3依赖性IL-1β产生和腹膜炎症。
DOI：
10.1136/annrheumdis-2013-204900
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发表时间：
2015-11
影响因子：
27.4
通讯作者：
Kay J
中科院分区：
文献类型：
--
作者：
Schmidt-Lauber C;Bossaller L;Abujudeh HH;Vladimer GI;Christ A;Fitzgerald KA;Latz E;Gravallese EM;Marshak-Rothstein A;Kay J
肾源性全身性纤维化(NSF)是一种进行性纤维化疾病，慢性肾脏病(CKD)患者在使用基于Gd的造影剂(GBCA)后可能会发生这种疾病。在GBCA的肾脏清除受损的背景下，Gd在各种组织中沉积，随后形成纤维化。然而，NSF中纤维化发生的确切机制尚不完全清楚。由于其他促纤维化因素，如二氧化硅或石棉，可激活结节样受体蛋白3(NLRP3)炎症小体，并启动IL-1β的释放，从而导致随后的纤维化发展，因此我们评估了GBCA对炎症小体激活的影响。将C57BL/6、Nlrp3−/−和Asc−/−小鼠的骨髓来源的巨噬细胞分别与3种含Gd化合物孵育后，用ELISA法和Western印迹法检测IL-1β的活化和分泌。用酶联免疫吸附试验、定量逆转录聚合酶链式反应和纳米串计数法研究IL-4和干扰素γ极化的巨噬细胞炎性小体的激活和调节。此外，对C57BL/6和Nlrp3−/−小鼠进行了腹腔注射。用GBCA和FACS分析腹膜炎性细胞的募集情况。游离Gd和Gbca在体外均能激活NLRP3炎症体，诱导IL-1β的分泌。在体内，Gd-DTPA还能诱导中性粒细胞和炎性单核细胞向腹膜募集。GD激活IL-4极化的巨噬细胞比干扰素γ极化的巨噬细胞更有效，后者优先表达已知的下调炎症体活性的基因。这些数据表明，从GBCA释放的Gd在适当的临床环境下触发了NLRP3依赖的炎症反应，导致纤维化。IL-4分化的巨噬细胞的优先激活与NSF以纤维化为主的表现相一致。
Nephrogenic systemic fibrosis (NSF) is a progressive fibrosing disorder that may develop in patients with chronic kidney disease (CKD) after administration of gadolinium-based contrast agents (GBCAs). In the setting of impaired renal clearance of GBCAs, gadolinium (Gd) deposits in various tissues and fibrosis subsequently develops. However, the precise mechanism by which fibrosis occurs in NSF is incompletely understood. Because other profibrotic agents, such silica or asbestos, activate the NOD-like receptor protein 3 (NLRP3) inflammasome and initiate IL-1β release with the subsequent development of fibrosis, we evaluated the effects of GBCAs on inflammasome activation. Bone marrow derived macrophages (BMDM) from C57BL/6, Nlrp3−/− and Asc−/− mice were incubated with three Gd-containing compounds and IL-1β activation and secretion was detected by ELISA and Western blot analysis. Inflammasome activation and regulation was investigated in IL-4- and IFNγ-polarized macrophages by ELISA, qRT-PCR and NanoString nCounter analysis. Furthermore, C57BL/6 and Nlrp3−/− mice were injected i.p. with GBCA and recruitment of inflammatory cells to the peritoneum was analyzed by FACS. Both free Gd and GBCAs activate the NLRP3 inflammasome and induce IL-1β secretion in vitro. Gd-DTPA also induces the recruitment of neutrophils and inflammatory monocytes to the peritoneum in vivo. Gd activated IL-4-polarized macrophages more effectively than IFNγ-polarized macrophages, which preferentially expressed genes known to downregulate inflammasome activity. These data suggest that Gd released from GBCAs triggers a NLRP3 inflammasome-dependent inflammatory response that leads to fibrosis in an appropriate clinical setting. The preferential activation of IL-4-differentiated macrophages is consistent with the predominantly fibrotic presentation of NSF.
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影响因子：
4.6
作者：
Koreishi, Aashiyana F.;Nazarian, Rosalynn M.;Kay, Jonathan
通讯作者：
Kay, Jonathan
影响因子：
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作者：
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通讯作者：
Katsikis, Peter D.
影响因子：
30.5
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影响因子：
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作者：
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通讯作者：
Jardine, Alan G.
影响因子：
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作者：
Jiménez, SA;Artlett, CM;Shanahan, JC
通讯作者：
Shanahan, JC