Inflammasome activation and IL-1β/IL-18 processing are influenced by distinct pathways in microglia.
Inflammasome activation and IL-1β/IL-18 processing are influenced by distinct pathways in microglia.
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DOI：
10.1111/j.1471-4159.2011.07481.x
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发表时间：
2011-11
影响因子：
4.7
通讯作者：
Kielian T
中科院分区：
文献类型：
--
作者：
Hanamsagar R;Torres V;Kielian T
小胶质细胞是抵抗中枢神经系统病原体入侵的重要先天免疫效应器，例如金黄色葡萄球菌（S. aureus），它是脑脓肿的常见病原体，以广泛的炎症和坏死为代表。 NLRP3 炎性体是一种蛋白质复合物，参与暴露于病原体和危险相关分子模式后的 IL-1β 和 IL-18 处理。尽管我们实验室之前的研究已经确定IL-1β是金黄色葡萄球菌激活的小胶质细胞的主要细胞因子产物，并且对于脑脓肿发展过程中引发保护性抗菌免疫至关重要，但负责细胞因子释放的分子机制仍有待确定。因此，在原代小胶质细胞中检查了 NLRP3 炎性体及其接头蛋白凋亡相关斑点样蛋白 (ASC) 在引发 IL-1β 和 IL-18 释放中的功能作用。有趣的是，我们发现在暴露于活金黄色葡萄球菌后，NLRP3 和 ASC 敲除 (KO) 小胶质细胞中 IL-1β 的产生显着减弱，但 IL-18 的产生并未显着减弱。 NLRP3 炎症小体的激活部分依赖于自分泌/旁分泌 ATP 释放以及活细菌产生的 α- 和 γ- 溶血素。组织蛋白酶 B 抑制剂可减弱 NLRP3 和 ASC KO 小胶质细胞释放的 IL-β，证明存在另一种独立于炎症小体的 IL-1β 加工机制。相反，小胶质细胞 IL-18 的分泌独立于组织蛋白酶 B 和炎症小体的作用。总的来说，这些结果表明小胶质细胞 IL-1β 加工受到多种途径的调节，并且与 IL-18 裂解所使用的机制不同。了解调节 IL-1β 产生的分子事件对于在 CNS 疾病期间调节这种有效的促炎细胞因子非常重要。
Microglia are important innate immune effectors against invading CNS pathogens, such as Staphylococcus aureus (S. aureus), a common etiological agent of brain abscesses typified by widespread inflammation and necrosis. The NLRP3 inflammasome is a protein complex involved in IL-1β and IL-18 processing following exposure to both pathogen- and danger-associated molecular patterns. Although previous studies from our laboratory have established that IL-1β is a major cytokine product of S. aureus-activated microglia and is pivotal for eliciting protective anti-bacterial immunity during brain abscess development, the molecular machinery responsible for cytokine release remains to be determined. Therefore, the functional role of the NLRP3 inflammasome and its adaptor protein apoptosis-associated speck-like protein (ASC) in eliciting IL-1β and IL-18 release was examined in primary microglia. Interestingly, we found that IL-1β, but not IL-18 production, was significantly attenuated in both NLRP3 and ASC knockout (KO) microglia following exposure to live S. aureus. NLRP3 inflammasome activation was partially dependent on autocrine/paracrine ATP release and α- and γ-hemolysins produced by live bacteria. A cathepsin B inhibitor attenuated IL-β release from NLRP3 and ASC KO microglia, demonstrating the existence of alternative inflammasome-independent mechanisms for IL-1β processing. In contrast, microglial IL-18 secretion occurred independently of cathepsin B and inflammasome action. Collectively, these results demonstrate that microglial IL-1β processing is regulated by multiple pathways and diverges from mechanisms utilized for IL-18 cleavage. Understanding the molecular events that regulate IL-1β production is important for modulating this potent proinflammatory cytokine during CNS disease.
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影响因子：
4.4
作者：
Esen, Nilufer;Kielian, Tammy
通讯作者：
Kielian, Tammy
影响因子：
--
作者：
Arostegui, Juan I.;Lopez Saldana, Ma Dolores;Yaguee, Jordi
通讯作者：
Yaguee, Jordi
影响因子：
3.5
作者：
Gravet, A;Colin, DA;Prévost, G
通讯作者：
Prévost, G
影响因子：
4.7
作者：
Esen, N;Tanga, FY;Kielian, T
通讯作者：
Kielian, T
影响因子：
32.4
作者：
Agostini, L;Martinon, F;Tschopp, J
通讯作者：
Tschopp, J