RRC ID 50300
Author Karasawa T, Kawashima A, Usui-Kawanishi F, Watanabe S, Kimura H, Kamata R, Shirasuna K, Koyama Y, Sato-Tomita A, Matsuzaka T, Tomoda H, Park SY, Shibayama N, Shimano H, Kasahara T, Takahashi M.
Title Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3 Inflammasome in Macrophages.
Journal Arterioscler Thromb Vasc Biol
Abstract 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-1β (interleukin 1β) 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-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.
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.
Volume 38(4)
Pages 744-756
Published 2018-4-1
DOI 10.1161/ATVBAHA.117.310581
PII ATVBAHA.117.310581
PMID 29437575
MeSH Acetyltransferases / genetics Acetyltransferases / metabolism Animals Cells, Cultured Crystallization Fatty Acid Elongases Fatty Acids / metabolism Fatty Acids / toxicity* Inflammasomes / agonists* Inflammasomes / metabolism Inflammation / chemically induced* Inflammation / genetics Inflammation / metabolism Inflammation / prevention & control Interleukin-1beta / genetics Interleukin-1beta / metabolism Lysosomes / drug effects Lysosomes / metabolism Lysosomes / pathology Macrophage Activation / drug effects* Macrophages, Peritoneal / drug effects* Macrophages, Peritoneal / metabolism Macrophages, Peritoneal / pathology Mice, Inbred C57BL Mice, Knockout NLR Family, Pyrin Domain-Containing 3 Protein / deficiency NLR Family, Pyrin Domain-Containing 3 Protein / genetics NLR Family, Pyrin Domain-Containing 3 Protein / metabolism* Signal Transduction / drug effects
IF 6.604
Times Cited 23
DNA material CS-CA-MCS (RDB05963)