Premium
Frontline Science: Acyl‐CoA synthetase 1 exacerbates lipotoxic inflammasome activation in primary macrophages
Author(s) -
Kalugotla Gowri,
He Li,
Weber Kassandra J.,
Daemen Sabine,
Reller Abigail,
Razani Babak,
Schilling Joel D.
Publication year - 2019
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3hi0219-045rr
Subject(s) - inflammasome , lysosome , biology , inflammation , microbiology and biotechnology , endoplasmic reticulum , lipid metabolism , macrophage , lipid droplet , autophagy , unfolded protein response , tlr4 , biochemistry , signal transduction , enzyme , immunology , apoptosis , in vitro
Obesity and diabetes are associated with macrophage dysfunction and increased NLRP3 inflammasome activation. Saturated fatty acids (FAs) are abundant in these metabolic disorders and have been associated with lysosome dysfunction and inflammasome activation in macrophages. However, the interplay between cellular metabolic pathways and lipid‐induced toxicity in macrophages remains poorly understood. In this study, we investigated the role of the lipid metabolic enzyme long chain acyl‐CoA synthetase (ACSL1) in primary macrophages. ACSL1 is upregulated in TLR4‐activated macrophages via a TIR (toll/IL‐1R) domain‐containing adapter inducing IFN‐β (TRIF)‐dependent pathway, and knockout of this enzyme decreased NLRP3 inflammasome activation. The mechanism of this response was not related to inflammasome priming, lipid uptake, or endoplasmic reticulum (ER) stress generation. Rather, ACSL1 was associated with mitochondria where it modulated fatty acid metabolism. The development of lysosome damage with palmitate exposure likely occurs via the formation of intracellular crystals. Herein, we provide evidence that loss of ACSL1 in macrophages decreases FA crystal formation thereby reducing lysosome damage and IL‐1β release. These findings suggest that targeting lipid metabolic pathways in macrophages may be a strategy to reduce lipotoxity and to decrease pathologic inflammation in metabolic disease.