期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 38, 期 4, 页码 744-756出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.117.310581
关键词
crystallization; cytokines; fatty acids; inflammasome; macrophages
资金
- Japan Society for the Promotion of Science
- Agency for Medical Research and Development-Core Research for Evolutional Science and Technology [JP17gm0610012]
- Ministry of Education, Culture, Sports, Science and Technology-supported program for the Strategic Foundation at Private Universities
- KAO Research Council for the Study of Healthcare Science
- Jichi Medical University Young Investigator Award
- Grants-in-Aid for Scientific Research [26105001, 16K19544, 15K21719] Funding Source: KAKEN
Objective 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-1 (interleukin 1) release and leads to inflammation, in this process. Therefore, we investigated the underlying mechanism by which SFAs trigger NLRP3 inflammasome activation. Approach and Results The treatment with SFAs, such as palmitic acid and stearic acid, promoted IL-1 release in murine primary macrophages while treatment with oleic acid inhibited SFA-induced IL-1 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-1 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-1 release via lysosomal dysfunction. Excess SFAs also induced crystallization and IL-1 release in vivo. Furthermore, SFA-derived crystals provoked acute inflammation, which was impaired in IL-1-deficient mice. Conclusions 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.
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