Pharmacological inhibition of fatty acid oxidation reduces atherosclerosis progression by suppression of macrophage NLRP3 inflammasome activation

Hohensinner, Philipp J.; Lenz, Max; Haider, Patrick; Mayer, Julia; Richter, Manuela; Kaun, Christoph; Goederle, L.; Brekalo, Mira; Salzmann, Manuel; Sharma, Smriti; Fischer, Michael B.; Stojković, Stefan; Ramsmayer, Daniel; Hengstenberg, Christian; Podesser, Bruno K.; Huber, Kurt; Binder, Christoph J.; Wojta, Johann; Speidl, Walter S.

doi:10.1016/j.bcp.2021.114634

Cited by 15 publications

(19 citation statements)

References 28 publications

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“…Afterwards, the cells were fixed and permeabilized using 4% formaldehyde/0.5% Triton‐X (both Sigma‐Aldrich, St. Louis, MO, USA). Intracellular NFκBp65 was stained using a rabbit primary antibody against p65 (10 μg/ml, Abcam, Cambridge, Cambridgeshire, United Kingdom) which was incubated for 1 h at room temperature as described previously 20 . A secondary donkey antibody against rabbit IgG (2.5 μg/ml, DyLight550, Thermo Fisher Scientific, Waltham, MA, USA) as well as phalloidin—iFluor488 (1:1000, Abcam, Cambridge, Cambridgeshire, United Kingdom) and DAPI (1 μg/ml, Sigma‐Aldrich, St. Louis, MO, USA) were added and slides were incubated for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Intracellular NFκBp65 was stained using a rabbit primary antibody against p65 (10 μg/ml, Abcam, Cambridge, Cambridgeshire, United Kingdom) which was incubated for 1 h at room temperature as described previously. 20 A secondary donkey antibody against rabbit IgG (2.5 μg/ ml, DyLight550, Thermo Fisher Scientific, Waltham, MA, USA) as well as phalloidin-iFluor488 (1:1000, Abcam, Cambridge, Cambridgeshire, United Kingdom) and DAPI (1 μg/ml, Sigma-Aldrich, St. Louis, MO, USA) were added and slides were incubated for 1 h at room temperature. The slides were covered with Aqueous Mounting Medium (Abcam, Cambridge, Cambridgeshire, United Kingdom) and confocal images were taken on a Zeiss LSM700 confocal laser microscope mounted with a ×63 oil objective (1.4 NA) using a pinhole of 1 airy unit.…”

Section: Histological Staining Of Isolated Human Monocytesmentioning

confidence: 99%

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Interleukin‐4 receptor alpha signaling regulates monocyte homeostasis

et al. 2022

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Interleukin‐4 (IL‐4) and its receptors (IL‐4R) promote the proliferation and polarization of macrophages. However, it is unknown if IL‐4R also influences monocyte homeostasis and if steady state IL‐4 levels are sufficient to affect monocytes. Employing full IL‐4 receptor alpha knockout mice (IL‐4Rα−/−) and mice with a myeloid‐specific deletion of IL‐4Rα (IL‐4Rαf/f LysMcre), we show that IL‐4 acts as a homeostatic factor regulating circulating monocyte numbers. In the absence of IL‐4Rα, murine monocytes in blood were reduced by 50% without altering monocytopoiesis in the bone marrow. This reduction was accompanied by a decrease in monocyte‐derived inflammatory cytokines in the plasma. RNA sequencing analysis and immunohistochemical staining of splenic monocytes revealed changes in mRNA and protein levels of anti‐apoptotic factors including BIRC6 in IL‐4Rα−/− knockout animals. Furthermore, assessment of monocyte lifespan in vivo measuring BrdU+ cells revealed that the lifespan of circulating monocytes was reduced by 55% in IL‐4Rα−/− mice, whereas subcutaneously applied IL‐4 prolonged it by 75%. Treatment of human monocytes with IL‐4 reduced the amount of dying monocytes in vitro. Furthermore, IL‐4 stimulation reduced the phosphorylation of proteins involved in the apoptosis pathway, including the phosphorylation of the NFκBp65 protein. In a cohort of human patients, serum IL‐4 levels were significantly associated with monocyte counts. In a sterile peritonitis model, reduced monocyte counts resulted in an attenuated recruitment of monocytes upon inflammatory stimulation in IL‐4Rαf/f LysMcre mice without changes in overall migratory function. Thus, we identified a homeostatic role of IL‐4Rα in regulating the lifespan of monocytes in vivo.

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Section: Methodsmentioning

confidence: 99%

Section: Histological Staining Of Isolated Human Monocytesmentioning

confidence: 99%

Interleukin‐4 receptor alpha signaling regulates monocyte homeostasis

et al. 2022

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“…In line with the enrichment analysis ( Figure 1D ), this result indicates that acetate might increase fatty acid oxidation. The later is known to induce IL-1β production by macrophages ( 36 , 37 ). However, blockage of fatty acid oxidation by etomoxir had no impact on IL-1β production induced by acetate ( Figure S8C ).…”

Section: Resultsmentioning

confidence: 99%

Acetate Improves the Killing of Streptococcus pneumoniae by Alveolar Macrophages via NLRP3 Inflammasome and Glycolysis-HIF-1α Axis

et al. 2022

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Short-chain fatty acids (SCFAs) are metabolites produced mainly by the gut microbiota with a known role in immune regulation. Acetate, the major SCFA, is described to disseminate to distal organs such as lungs where it can arm sentinel cells, including alveolar macrophages, to fight against bacterial intruders. In the current study, we explored mechanisms through which acetate boosts macrophages to enhance their bactericidal activity. RNA sequencing analyses show that acetate triggers a transcriptomic program in macrophages evoking changes in metabolic process and immune effector outputs, including nitric oxide (NO) production. In addition, acetate enhances the killing activity of macrophages towards Streptococcus pneumoniae in an NO-dependent manner. Mechanistically, acetate improves IL-1β production by bacteria-conditioned macrophages and the latter acts in an autocrine manner to promote NO production. Strikingly, acetate-triggered IL-1β production was neither dependent of its cell surface receptor free-fatty acid receptor 2, nor of the enzymes responsible for its metabolism, namely acetyl-CoA synthetases 1 and 2. We found that IL-1β production by acetate relies on NLRP3 inflammasome and activation of HIF-1α, the latter being triggered by enhanced glycolysis. In conclusion, we unravel a new mechanism through which acetate reinforces the bactericidal activity of alveolar macrophages.

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“…Conversely, downregulation of CPT1A and the consequent inhibition of FAO blunts NLRP3 inflammasome activation in Hif2a −/macrophages and alleviates obesity-induced insulin resistance in myeloid-specific Hif2a knockout mice relative to controls [77]. Accordingly, pharmacological blockade of FAO in macrophages has restrained the progression of atherosclerosis and gouty inflammation in mice [78,79]. FAs can be anabolized de novo in the cell cytoplasm and endoplasmic reticulum.…”

Section: Inflammasome Regulation By Lipid Pathwaysmentioning

confidence: 99%