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Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):744-756. doi: 10.1161/ATVBAHA.117.310581. Epub 2018 Feb 8.

Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3 Inflammasome in Macrophages.

Author information

1
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.). tdys.karasawa@jichi.ac.jp masafumi2@jichi.ac.jp.
2
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.).

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.

KEYWORDS:

crystallization; cytokines; fatty acids; inflammasome; macrophages

PMID:
29437575
DOI:
10.1161/ATVBAHA.117.310581
[Indexed for MEDLINE]

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