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Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect [scRNA-Seq 2]

ABSTRACT: Multiple mechanisms of immunity must be coordinated for the successful defense against a comprehensive range of pathogens, yet how broad-spectrum antipathogens act through these mechanisms remains largely elusive. Here, we used systems biology approaches to understand human immune cell reorganization at the single-cell level using a novel silane derivative, K21, which is effective against viruses, bacteria, and fungal infections. K21 significantly induced pro-inflammatory macrophages originating from both M1 and M2c macrophages without changing their ability to secrete respective cytokines. K21 decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, currently referred to as M4 macrophages, that play a critical role in solid cancers and fibrosis. K21-mediated immune cell remodeling was observed only in a complex multicellular co-culture environment, suggesting the interplay of various cell-derived components. K21 improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of the mechanism. Our work demonstrates that a drug that remodels metabolism can shape the immune cell repertoire, which could aid in the development of more effective antimicrobials and potentially prevent the emergence of drug-resistant pathogens.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301385 | GEO | 2025/08/13

REPOSITORIES: GEO

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Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect [scRNA-Seq]

Project description:Multiple mechanisms of immunity must be coordinated for the successful defense against a comprehensive range of pathogens, yet how broad-spectrum antipathogens act through these mechanisms remains largely elusive. Here, we used systems biology approaches to understand human immune cell reorganization at the single-cell level using a novel silane derivative, K21, which is effective against viruses, bacteria, and fungal infections. K21 significantly induced pro-inflammatory macrophages originating from both M1 and M2c macrophages without changing their ability to secrete respective cytokines. K21 decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, currently referred to as M4 macrophages, that play a critical role in solid cancers and fibrosis. K21-mediated immune cell remodeling was observed only in a complex multicellular co-culture environment, suggesting the interplay of various cell-derived components. K21 improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of the mechanism. Our work demonstrates that a drug that remodels metabolism can shape the immune cell repertoire, which could aid in the development of more effective antimicrobials and potentially prevent the emergence of drug-resistant pathogens.

2025-08-13 | GSE301383 | GEO

Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect

Project description:Multiple mechanisms of immunity must be coordinated for the successful defense against a comprehensive range of pathogens, yet how broad-spectrum antipathogens act through these mechanisms remains largely elusive. Here, we used systems biology approaches to understand human immune cell reorganization at the single-cell level using a novel silane derivative, K21, which is effective against viruses, bacteria, and fungal infections. K21 significantly induced the differentiation of monocytes into macrophages and dendritic cells (MoDCs), as well as the differentiation of natural killer cells (NK cells). K21 decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, currently referred to as M4 macrophages, that play a critical role in solid cancers and fibrosis. K21-mediated immune cell remodeling was observed only in a complex multicellular co-culture environment, suggesting the interplay of various cell-derived components. K21 improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of mechanism. Our work demonstrates that a drug that remodels metabolism can shape the immune cell repertoire, which could help develop more effective antimicrobials and potentially prevent the development of drug-resistance pathogens.

2025-08-13 | GSE296571 | GEO

microRNA expression profiling of polarized macrophages

Project description:microRNAs are small non-coding RNAs that regulate gene expression at a post-translational level, and play a crucial role in the development of cells of the immune system. Macrophages are essential for generating inflammatory reactions upon tissue damage and encountering of invading pathogens, yet modulation of their immune responses is critical for maintaining tissue homeostasis. Macrophages can present different phenotypes, depending on the cytokine environment they encounter in the affected tissues. In this study, we have identified expression signatures of miRNAs that are differentially regulated during maturation of monocytes and polarization of macrophages by cytokines. We present a comprehensive characterization of miRNA expression in human monocytes and M1, M2a and M2c polarized macrophages, using next-generation Sequencing by Oligonucleotide Ligation and Detection (SOLiD). We have analyzed freshly isolated human monocytes and 5 day monocyte-derived macrophages unstimulated, or stimulated with IFNgamma+TNFalpha (M1), IL-4 (M2a) or IL-10 (M2c).

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2015-03-12 | E-GEOD-57614 | biostudies-arrayexpress

CXCL4 induces a unique transcriptome in monocyte-derived macrophages

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Project description:Macrophages are important effector cells of the immune system and play an important role in mounting inflammatory responses. Macrophages can be activated by different stimuli in the tissue, either by cytokines produced by T helper cells (M1 or M2 polarization) or by the pathogens they encounter. Macrophages are also important target cells of HIV-1 and are preferentially infected by CCR5-using viruses. In this study, we investigated the ability of HIV-1 to induce changes in gene expression in unpolarized macrophages as well as in M1 or M2 polarized cells. We observed that CCR5-using HIV-1 regulates the expression of genes that are also regulated by IL-4 in macrophages. Genes regulated by HIV-1 infection and IL-4 polarization are involved in dampening pro-inflammatory responses in macrophages, which may facilitate HIV-1 to escape from detection by other immune cells. We also observed that changes in macrophage gene expression triggered by CCR5-using HIV-1 differed from those regulated by a CXCR4-using virus. This indicates that CCR5-using HIV-1 may be able to modulate macrophage gene expression to achieve successful replication. Our results provide insight in the complex interplay between HIV-1 and cells of the immune system. Polarized macrophages were obtained by stimulation of primary human monocytes with IFN-gamma (250 U/ml) in combination with TNF-alpha (12.5 ng/ml) (M1), IL-4 (50 ng/ml) (M2a), IL-10 (50 ng/ml) (M2c) for 5 days. Cells were inoculated for 24 hours with one of two HIV-1 strains (CCR5 or CXCR4 using HIV1) or their non replicating counterparts (heat inactivated virus). Macrophages that were not stimulated wiht cyokines or inoculates with HIV-1 were used as control. A total of 16 treatment conditions were tested in triplicate, for a total of 48 samples analysed.

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