The Role of the NLRP3 Inflammasome in Fibrosis.
The Role of the NLRP3 Inflammasome in Fibrosis.
复制标题
DOI：
10.2174/1874312901206010080
复制
发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Artlett CM
中科院分区：
文献类型：
--
作者：
Artlett CM
纤维化导致胶原蛋白在器官和组织中沉积。由此产生的病理学导致其所表现的器官功能丧失，并且这种功能丧失调节该个体的发病率和死亡率。事实上，西方世界大约 45% 的死亡可归因于纤维化，并且 FDA 没有批准用于治疗纤维化的药物。最近对炎症小体的发现引发了大量研究，调查多种病原体相关疾病中的炎症信号传导途径。许多研究都集中在 NLRP3 炎症小体上，这种炎症小体被多种细胞警报信号激活。一旦激活，caspase-1 就会被裂解，诱导 IL-1β 和 IL-18 的分泌，这些信号有助于清除入侵的生物体。然而，随着对炎症小体认识的扩展，人们发现它可以直接控制胶原蛋白的合成，导致肺、肝、心脏和皮肤等组织中胶原蛋白的沉积增加。缺乏炎性体衔接蛋白 ASC 的小鼠在接触博莱霉素时未能发生纤维化。抑制纤维化疾病系统性硬化症患者成纤维细胞中的 caspase-1 活性，减少肌成纤维细胞中的胶原合成和 α-平滑肌肌动蛋白表达。综上所述，这些观察结果表明炎症小体可以驱动纤维化反应，并为识别新疗法铺平道路。
Fibrosis leads to the deposition of collagens in organs and tissues. The resulting pathology induces a loss of function in the organ it is manifested in and this loss of function modulates the morbidity and mortality in that individual. Indeed, approximately 45% of all deaths in the Western world can be attributed to fibrosis and there are no FDA approved drugs for the treatment of fibrosis. The recent discovery of the inflammasome has led to a plethora of studies investigating this inflammatory signaling pathway in a wide variety of pathogen associated diseases. Many studies have focused on the NLRP3 inflammasome and this inflammasome is activated by a wide variety of cellular alarm signals. Once activated, caspase-1 is cleaved, inducing the secretion of IL-1β and IL-18 that signal to aid in the clearance of invading organisms. However, as the knowledge of the inflammasome has expanded, it was found that it can directly control collagen synthesis, leading to the increased deposition of collagens in the tissues such as the lung, liver, heart, and skin. Mice lacking the inflammasome adaptor protein, ASC, failed to become fibrotic when exposed to bleomycin. Inhibition of caspase-1 activity in fibroblasts from patients with the fibrotic disease systemic sclerosis, decreased collagen synthesis and reduced α-smooth muscle actin expression in myofibroblasts. Taken together, these observations suggest that the inflammasome can drive the fibrotic response and paves the way for novel therapeutics to be identified.