From the Division of Inflammation Research, Center for Molecular Medicine (T. Karasawa, A.K., F.U.-K., S.W., H.K., R.K., K.S., Y.K., T. Kasahara, M.T.) and Division of Biophysics, Department of Physiology (A.S.-T., N.S.), Jichi Medical University, Tochigi, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, Japan (T.M., H.S.); Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (H.T.); and Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan (S.-Y.P.).
Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):744-756. doi: 10.1161/ATVBAHA.117.310581. Epub 2018 Feb 8.
Inflammation provoked by the imbalance of fatty acid composition, such as excess saturated fatty acids (SFAs), is implicated in the development of metabolic diseases. Recent investigations suggest the possible role of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3) inflammasome, which regulates IL-1β (interleukin 1β) release and leads to inflammation, in this process. Therefore, we investigated the underlying mechanism by which SFAs trigger NLRP3 inflammasome activation.
The treatment with SFAs, such as palmitic acid and stearic acid, promoted IL-1β release in murine primary macrophages while treatment with oleic acid inhibited SFA-induced IL-1β release in a dose-dependent manner. Analyses using polarized light microscopy revealed that intracellular crystallization was provoked in SFA-treated macrophages. As well as IL-1β release, the intracellular crystallization and lysosomal dysfunction were inhibited in the presence of oleic acid. These results suggest that SFAs activate NLRP3 inflammasome through intracellular crystallization. Indeed, SFA-derived crystals activated NLRP3 inflammasome and subsequent IL-1β release via lysosomal dysfunction. Excess SFAs also induced crystallization and IL-1β release in vivo. Furthermore, SFA-derived crystals provoked acute inflammation, which was impaired in IL-1β-deficient mice.
These findings demonstrate that excess SFAs cause intracellular crystallization and subsequent lysosomal dysfunction, leading to the activation of the NLRP3 inflammasome, and provide novel insights into the pathogenesis of metabolic diseases.
脂肪酸组成失衡所引发的炎症，如过量的饱和脂肪酸（SFAs），与代谢疾病的发展有关。最近的研究表明，核苷酸结合寡聚化结构域、富含亮氨酸重复和pyrin 结构域蛋白 3（NLRP3）炎症小体可能在这一过程中发挥作用，该炎症小体调节白细胞介素 1β（IL-1β）的释放并导致炎症。因此，我们研究了 SFAs 触发 NLRP3 炎症小体激活的潜在机制。
棕榈酸和硬脂酸等 SFAs 的处理促进了鼠原代巨噬细胞中 IL-1β 的释放，而油酸以剂量依赖性方式抑制 SFA 诱导的 IL-1β 释放。偏光显微镜分析显示，SFAs 处理的巨噬细胞中发生了细胞内结晶。与 IL-1β 释放一样，油酸的存在抑制了细胞内结晶和溶酶体功能障碍。这些结果表明，SFAs 通过细胞内结晶激活 NLRP3 炎症小体。事实上，SFA 衍生的晶体通过溶酶体功能障碍激活 NLRP3 炎症小体和随后的 IL-1β 释放。过量的 SFAs 也在体内诱导结晶和 IL-1β 释放。此外，SFA 衍生的晶体引发了急性炎症，而这种炎症在缺乏白细胞介素 1β 的小鼠中受到损害。
这些发现表明，过量的 SFAs 导致细胞内结晶和随后的溶酶体功能障碍，从而激活 NLRP3 炎症小体，并为代谢疾病的发病机制提供了新的见解。
