Frontline Science: Acyl-CoA synthetase 1 exacerbates lipotoxic inflammasome activation in primary macrophages

Abstract

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 TLR4activated macrophages via a TIR (toll/IL-1R) domain-containing adapter inducing IFN-(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-1 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. K E Y W O R D Sdiabetes, inflammation, metabolism, monocyte/macrophage

Growing evidence for a role for acyl-CoA synthetase 1 in immunometabolism

“…The study by Kalugotla and colleagues adds increased evidence that ACSL1 is involved in immunometabolism in macrophages . Like previous studies, the authors first show that inflammatory mediators, in this case LPS, increase ACSL1 expression in macrophages, and that LPS‐mediated induction of ACSL1 occurs through a TRIF‐dependent mechanism, recapitulating previous studies .…”

“…One of these processes is the thioesterification of free fatty acids to generate acyl‐CoAs in macrophages. This process has been investigated by Kalugotla and colleagues in a manuscript published in this issue of the Journal of Leukocyte Biology . Most biological effects of fatty acids depend on their conversion to acyl‐CoA derivatives.…”

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

“…Recently, in breast cancer cells, ACSL1 has been reported to regulate TNF-α-induced production of granulocyte-macrophage colony-stimulating factor (GM-CSF) [81], an essential growth factor for myeloid cell differentiation. Interestingly, in response to palmitate, selective deletion of ACSL1 in myeloid cells reduces lysosome-dependent NLRP3 inflammasome activation and the production of IL-1β [23], an inflammatory cytokine that is tightly associated with tumor progression, suggesting the role of palmitate in cancer development. Although emerging evidence shows the correlation between palmitate-related inflammation and cancer development, the mechanism by which palmitate modulates the activity and/or immunological phenotypes of innate immune cells in the tumor microenvironment during tumor development remains to be further elucidated.…”

“…ACSL1 catalyzes the conversion of several fatty acids to fatty acyl-CoAs, which enables their intracellular activity. Deletion of ACSL1 in macrophages results in reduced palmitate crystals and subsequent inflammasome-induced IL-1β release [23], suggesting that ACSL1-dependent conversion of palmitate to palmitoyl-CoA plays a critical role in palmitate-induced crystallization and contributes to lipotoxic inflammasome activation. In addition, myeloid cell-specific deletion of ACSL1 in a diabetic mouse model prevented the formation of the inflammatory phenotype of macrophages, which is associated with diabetes [91].…”

“…In addition, the crystals formed from saturated fatty acids, including palmitate, have been implicated in lysosome damage-associated NLRP3 inflammasome activation and IL-1β production in macrophages [18]. Likewise, Kalugotla et al provided evidence showing that the deletion of acyl-CoA synthetase 1 (ACSL1), an enzyme responsible for the esterification of saturated fatty acids, reduces fatty acid crystal formation, thereby decreasing lysosome damage and IL-1β release [23]; this observation suggests the important role of lysosome integrity in the regulation of palmitate-induced inflammasome activation. Moreover, loss of NLRP3 abrogates palmitate-induced IL-1β production in macrophages, suggesting that palmitate regulates NLRP3 inflammasome-mediated cytokine production [24].…”