Oridonin suppresses particulate-induced NLRP3-independent IL-1α release to prevent crystallopathy in the lung
Oridonin suppresses particulate-induced NLRP3-independent IL-1α release to prevent crystallopathy in the lung
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DOI：
10.1093/intimm/dxac018
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发表时间：
2022-07-17
影响因子：
4.4
通讯作者：
Saitoh, Tatsuya
中科院分区：
文献类型：
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作者：
Ikoma, Kenta;Takahama, Michihiro;Saitoh, Tatsuya
人体暴露于工业、环境或内源性来源的各种颗粒物。侵入性或内在颗粒可通过异常激活免疫系统诱导炎症，从而引起晶体病。当免疫细胞如巨噬细胞吞噬颗粒时，它们的吞噬溶酶体膜受到机械损伤，最终导致伴随炎性细胞因子（包括白细胞介素（IL）-1 α和IL-1 β）释放的pyroptotic细胞死亡。含有3个蛋白结构域的结节样受体家族（NLRP 3）炎性体负责颗粒诱导的IL-1 β释放，因此被认为是炎症介导的晶体病的潜在治疗靶点。然而，IL-1 α在颗粒刺激后以NLRP 3炎性小体非依赖性方式释放，并在疾病发展中起关键作用。因此，应该开发通过全面抑制颗粒诱导的反应（包括IL-1 β释放和IL-1 α释放）来发挥有效抗炎作用的药物。在这里，我们发现，冬凌草甲素，一种从香茶菜中分离的二萜类化合物，强烈抑制颗粒诱导的细胞死亡，伴随着小鼠和人巨噬细胞中IL-1 α和IL-1 β的释放。冬凌草甲素减少颗粒诱导的巨噬细胞吞噬溶酶体膜损伤，而不影响颗粒的吞噬作用。此外，冬凌草甲素治疗显著抑制二氧化硅颗粒诱导的肺炎的症状，这归因于独立于NLRP 3的IL-1 α的释放。因此，冬凌草甲素是一种潜在的先导化合物，用于开发有效的治疗晶体病归因于NLRP 3依赖性以及NLRP 3非依赖性炎症。
The human body is exposed to various particulates of industrial, environmental, or endogenous origin. Invading or intrinsic particulates can induce inflammation by aberrantly activating the immune system, thereby causing crystallopathies. When immune cells such as macrophages phagocytose the particulates, their phagolysosomal membranes undergo mechanical damage, eventually leading to pyroptotic cell death accompanied by the release of inflammatory cytokines, including interleukin (IL)-1 alpha and IL-1 beta. The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is responsible for particulate-induced IL-1 beta release and is therefore regarded as a potential therapeutic target for inflammation-mediated crystallopathies. However, IL-1 alpha is released after particulate stimulation in an NLRP3 inflammasome-independent manner and plays a critical role in disease development. Therefore, drugs that exert potent anti-inflammatory effects by comprehensively suppressing particulate-induced responses, including IL-1 beta release and IL-1 alpha release, should be developed. Here, we found that oridonin, a diterpenoid isolated from Isodon japonicus HARA, strongly suppressed particulate-induced cell death, accompanied by the release of IL-1 alpha and IL-1 beta in mouse and human macrophages. Oridonin reduced particulate-induced phagolysosomal membrane damage in macrophages without affecting phagocytosis of particulates. Furthermore, oridonin treatment markedly suppressed the symptoms of silica particle-induced pneumonia, which was attributed to the release of IL-1 alpha independently of NLRP3. Thus, oridonin is a potential lead compound for developing effective therapeutics for crystallopathies attributed to NLRP3-dependent as well as NLRP3-independent inflammation.