PPARγ-Mediated Ferroptosis in Macrophages Enhances Persistent Pulmonary Infction by Mycobacterium tuberculosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275146 | GEO | 2026/04/24
REPOSITORIES: GEO
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Project description:Ferroptosis is an iron-dependent programmed cell death caused by lipid peroxidation. Emerging evidence suggests several pathogens manipulate ferroptosis as a way for pathogen propagation, but the underlying mechanisms remain largely elusive. Here, we report that PtpA, secreted by intracellular pathogen Mycobacterium tuberculosis (Mtb), is a ferroptosis inducer during infection. Mechanistically, Mtb PtpA entries into the nucleus through the RaDAR pathway depending on the conserved cysteine 11 site, but not canonical ARs motif. Then, PtpA functions as an adaptor to increase the affinity between protein arginine methyltransferase 6 (PRMT6) with its substrate histone H3, thus promoting the asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a), leading to repression of GPX4 gene expression and the ensuing ferroptosis. Accordingly, disrupting nucleus entry site or PRMT6-interacting motif of PtpA markedly eliminates the PtpA-induced ferroptosis in host cells. These findings find a new motif involved in intracellular pathogens effectors for entering host nucleus, and reveal an unrecognized regulatory role of PtpA as an activator of methyltransferases PRMT6 to promote ferroptosis in host nuclear, providing fresh insights into the mechanism of Mtb-induced cell death.
2023-02-04 | GSE199069 | GEO
Project description:Background. An exacerbated oxidative stress response can regulate cellular necrosis by triggering lipid peroxidation in an iron-dependent manner and this form of necrotic death has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. Here we examined the role of Bach1, a transcription factor that represses a major set of antioxidant genes, in regulating host resistance to Mtb. We found that BACH1 expression is associated with and predicts active pulmonary tuberculosis in humans. In response to Mtb infection in vitro and in vivo, ablation of Bach1 increased the levels of glutathione as well as enhanced the expression of Gpx4, an enzyme that regulates lipid peroxidation. Consistent with these observations, Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death and infected Bach1-deficient mice displayed a striking reduction in bacterial loads as well as pulmonary necrosis and lipid peroxidation accompanied by enhanced survival. In addition, single-cell RNAseq analysis of the lungs of Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with suppression of ferroptosis. Finally, deletion of Bach1 in B6.Sst1S mice, an inbred strain that exhibits the necrotic lung pathology similar to that seen in human TB, enhanced host resistance to Mtb while significantly reducing tissue necrosis. These findings identify Bach1 and its regulation of the oxidative stress response as an important modulator of cellular and tissue necrosis as well as host resistance in Mtb infection.
2023-09-07 | GSE236853 | GEO
Project description:PPARγ is known for its anti-inflammatory actions in macrophages. However, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation is not completely understood. We show that lung and spleen macrophages constitutively expressed PPARγ, while other macrophage populations did not. Recruitment of monocytes to sites of inflammation was associated with induction of PPARγ as they differentiated to macrophages. Its absence in these macrophages led to failed resolution of inflammation, characterized by persistent, low-level recruitment of leukocytes. Conversely, PPARγ agonists supported an earlier cessation in leukocyte recruitment during resolution of acute inflammation and likewise suppressed monocyte recruitment to chronically inflamed atherosclerotic vessels. In the steady state, PPARγ deficiency in macrophages had no obvious impact in the spleen but profoundly altered cellular lipid homeostasis in lung macrophages. Reminiscent of pulmonary alveolar proteinosis, LysM-Cre x PPARγflox/flox mice displayed mild leukocytic inflammation in the steady-state lung and succumbed faster to mortality upon infection with S. pneumoniae. Surprisingly, this mortality was not due to overly exuberant inflammation, but instead to impaired bacterial clearance. Thus, in addition to its anti-inflammatory role in promoting resolution of inflammation, PPARγ sustains functionality in lung macrophages and thereby has a pivotal role in supporting pulmonary host defense. The two major subsets of monocytes (Ly-6C+ and Ly-6Clo) from 12-week old C57Bl/6 mice were sorted and the RNA extracted and hybridized to Affymetrix GeneChip® 430 2.0 arrays. We pooled leukocytes from 5 mice for each sort and sorted 3 to 4 separate times for 3 to 4 biological replicates.
2012-10-03 | E-GEOD-32034 | biostudies-arrayexpress
Project description:PPARγ-Mediated Ferroptosis in Macrophages Enhances Persistent Pulmonary Infction by Mycobacterium tuberculosis
| PRJNA1149689 | ENA
Project description:Mycobacterium tuberculosis (Mtb)-induced shifts in macrophage metabolism are an accepted central infection paradigm. Mtb-infected murine lung tissue exhibits gene expression changes consistent with classic Warburg metabolism and Mtb-infected murine macrophages undergo TCA cycle remodeling. Human macrophages also respond energetically to Mtb infection, however, interestingly the phenotypic nature of this response appears to vary depending on the viability of infection. Despite the overwhelming consensus that metabolic changes are critical to the host response to infection, we have little understanding of the metabolic transcriptional landscape of virulent Mtb-infected human alveolar macrophages (AM), the sentinel pulmonary immune cell during Mtb infection. Further still, whether the human AM undergoes glycolytic reprogramming and TCA cycle remodeling during virulent Mtb infection remains undefined; as is suggested to occur in circulating Mtb-infected human macrophages. Here, we aimed to characterise the metabolic transcriptional profile of virulent Mtb-infected human AM. We hypothesised that infection would induce the transcriptome of Warburg metabolism (characterised by aerobic glycolysis), TCA cycle remodeling, and reduce expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS).
2025-05-15 | GSE266414 | GEO
Project description:Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), capable of manipulating and circumventing the host's immune system to establish infection. Ubiquitination plays a crucial role in the host's response to pathogens; however, the global alterations in protein ubiquitination during Mtb infection remain poorly understood. To elucidate the regulatory roles of ubiquitination in the immune response to Mtb, we investigated the ubiquitome of human macrophages following Mtb infection.
2025-08-21 | PXD063016 | Pride
Project description:Latent tuberculosis infection (LTBI) relies on a homeostasis of macrophages and Mycobacterium tuberculosis (Mtb). The small heat shock protein, Mtb Hsp16.3 (also known as latency-associated antigen), plays an important role in Mtb persistence within macrophages. However, the mechanism of LTBI remains elusive. The aim of this study was to delineate LTBI-related miRNA expression in U937 macrophages expressing Mtb Hsp16.3 protein. This study intends to explore the potential function of miRNAs in the interaction of macrophages with Mtb Hsp16.3 and provide insights for investigating the role of macrophage homeostasis in LTBI.
2014-03-17 | GSE54630 | GEO
Project description:PPARγ is known for its anti-inflammatory actions in macrophages. However, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation is not completely understood. We show that lung and spleen macrophages constitutively expressed PPARγ, while other macrophage populations did not. Recruitment of monocytes to sites of inflammation was associated with induction of PPARγ as they differentiated to macrophages. Its absence in these macrophages led to failed resolution of inflammation, characterized by persistent, low-level recruitment of leukocytes. Conversely, PPARγ agonists supported an earlier cessation in leukocyte recruitment during resolution of acute inflammation and likewise suppressed monocyte recruitment to chronically inflamed atherosclerotic vessels. In the steady state, PPARγ deficiency in macrophages had no obvious impact in the spleen but profoundly altered cellular lipid homeostasis in lung macrophages. Reminiscent of pulmonary alveolar proteinosis, LysM-Cre x PPARγflox/flox mice displayed mild leukocytic inflammation in the steady-state lung and succumbed faster to mortality upon infection with S. pneumoniae. Surprisingly, this mortality was not due to overly exuberant inflammation, but instead to impaired bacterial clearance. Thus, in addition to its anti-inflammatory role in promoting resolution of inflammation, PPARγ sustains functionality in lung macrophages and thereby has a pivotal role in supporting pulmonary host defense.
2012-10-03 | GSE32034 | GEO
Project description:Exacerbated oxidative stress response is known to regulate cellular necrosis by triggering lipid peroxidation in an iron-dependent manner and this form of necrotic death has been implicated in Mycobacterium tuberculosis (Mtb) infection and disease. Here we examined the role of Bach1, a transcription factor that represses a major set of antioxidant genes, in regulating host resistance to Mtb. In response to Mtb infection in vitro and in vivo, ablation of Bach1 increased the levels of glutathione as well as enhanced the expression of Gpx4, an enzyme that regulates lipid peroxidation. Consistent with these observations, Bach1-/- macrophages exhibited increased resistance to Mtb-induced necrosis and infected Bach1-deficient mice displayed a striking reduction in bacterial loads as well as pulmonary necrosis and lipid peroxidation reflected in their enhanced survival. In addition, single-cell RNAseq analysis of the lungs of Mtb-infected Bach1-/- mice revealed an enrichment of a gene signature associated with protection against ferroptotic cell death. Finally, deletion of Bach1 in B6.Sst1S mice, an inbred strain that recapitulates the necrotic lung pathology seen in human TB, enhanced host resistance to Mtb while significantly reducing tissue necrosis. These findings identify Bach1 as an important regulator of cellular and tissue necrosis in Mtb infection and as such a potential target for host-direct therapy of tuberculosis.
2023-06-30 | GSE236053 | GEO
Project description:The innate immune system provides the first response to pathogen infection and orchestrates the activation of the adaptive immune system. Though a large component of the innate immune response is common to all infections, pathogen-specific innate immune responses have been documented as well. The innate immune response is thought to be especially critical for fighting infection with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB). While TB can be a deadly disease, only 5-10% of individuals infected with MTB develop active disease, and this inter-individual variation is, at least partly, heritable. Studies of inter-individual variation in the innate immune response to MTB infection may therefore shed light on the genetic basis for variation in susceptibility to TB. Yet, to date, we still do not know which properties of the innate immune response are specific to MTB infection and which represent a general response to pathogen infection. To begin addressing this gap, we infected macrophages with eight different bacterial pathogens, including different MTB strains and related mycobacteria, and studied the transcriptional response to infection. We found that although the gene expression changes were largely consistent across the bacterial infection treatments, we were able to identify a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. Genetic variants that are associated with regulatory differences in these genes should be considered candidate loci for explaining inter-individual susceptibility TB. RNA-seq of monocyte-derived macrophages isolated from 6 healthy European males at 4, 18, and 48 hours post-infection with the following 8 bacteria: Mycobacterium tuberculosis (MTB) H37Rv, Mycobacterium tuberculosis GC1237, MTB GC1237, bacillus Calmette-Guérin (BCG), Mycobacterium smegmatis, Yersinia pseudotuberculosis, Salmonella typhimurium, and Staphylococcus epidermidis. table-s1.txt is a tab-delimited text file that contains the batch-corrected log2 counts per million for each of the 156 samples, as well as the Ensembl gene ID and gene name. BCG = bacillus Calmette-Guérin GC = Mycobacterium tuberculosis GC1237 Rv = Mycobacterium tuberculosis (MTB) H37Rv Rv+ = heat-inactivated MTB H37Rv Salm = Salmonella typhimurium Smeg = Mycobacterium smegmatis Staph = Staphylococcus epidermidis Yers = Yersinia pseudotuberculosis
2015-03-31 | E-GEOD-67427 | biostudies-arrayexpress