Imipramine Treatment Alters Sphingomyelin, Cholesterol, and Glycerophospholipid Metabolism in Isolated Macrophage Lysosomes
Jacob M. Albright,
Matthew J. Sydor,
Jonathan Shannahan
et al.
Abstract:Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such as nutrient sensing, intracellular signaling, and lipid metabolism. Due to these central roles, lysosome dysfunction can lead to deleterious outcomes, including the accumulation of cytotoxic material, inflammation, and cell death. We previously reported that cationic amphiphilic drugs, such as imipramine, alter pH and lipid metabolism within m… Show more
Alterations in the macrophage metabolome greatly influence macrophage differentiation, subsequently impacting the development of diverse clinical diseases. Although S100A4 is a crucial factor in conditioned macrophage movement and inflammatory cell recruitment, its metabolism-mediated mechanism in regulating macrophage differentiation remains unclear. Here, we generated mice with a macrophage-specific S100A4 deletion by crossing C57BL/6J-S100a4 em1(flox)Cya mice with Lyz2-cre mice. Subsequently, macrophages were isolated from these mice, and heterozygous mouse macrophages served as controls for metabolomic analysis. The S100A4 deletion significantly influenced metabolic pathways, such as those involving lysophosphatidylserine, ceramide, and L-glutamate, which are implicated in modulating macrophage differentiation. This work elucidates the metabolic intricacies associated with the S100A4-mediated regulation of macrophage differentiation and provides a valuable reference for future investigations in this field.
Alterations in the macrophage metabolome greatly influence macrophage differentiation, subsequently impacting the development of diverse clinical diseases. Although S100A4 is a crucial factor in conditioned macrophage movement and inflammatory cell recruitment, its metabolism-mediated mechanism in regulating macrophage differentiation remains unclear. Here, we generated mice with a macrophage-specific S100A4 deletion by crossing C57BL/6J-S100a4 em1(flox)Cya mice with Lyz2-cre mice. Subsequently, macrophages were isolated from these mice, and heterozygous mouse macrophages served as controls for metabolomic analysis. The S100A4 deletion significantly influenced metabolic pathways, such as those involving lysophosphatidylserine, ceramide, and L-glutamate, which are implicated in modulating macrophage differentiation. This work elucidates the metabolic intricacies associated with the S100A4-mediated regulation of macrophage differentiation and provides a valuable reference for future investigations in this field.
Mass spectrometry imaging (MSI) is essential for visualizing drug distribution, metabolites, and significant biomolecules in pharmacokinetic studies. This study mainly focuses on imipramine, a tricyclic antidepressant that affects endogenous metabolite concentrations. The aim was to use atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI)-MSI combined with different dimensionality reduction methods to examine the distribution and impact of imipramine on endogenous metabolites in the brains of treated wild-type mice. Brain sections from both control and imipramine-treated mice underwent AP-MALDI-MSI. Dimensionality reduction methods, including principal component analysis, multivariate curve resolution, and sparse autoencoder (SAE), were employed to extract valuable information from the MSI data. Only the SAE method identified phosphorylcholine (ChoP) as a potential marker distinguishing between the control and treated mice brains. Additionally, a significant decrease in ChoP accumulation was observed in the cerebellum, hypothalamus, thalamus, midbrain, caudate putamen, and striatum ventral regions of the treated mice brains. The application of dimensionality reduction methods, particularly the SAE method, to the AP-MALDI-MSI data is a novel approach for peak selection in AP-MALDI-MSI data analysis. This study revealed a significant decrease in ChoP in imipramine-treated mice brains.
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