Similar Datasets
Project description:Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow progenitors are well-established mechanisms underpinning durable TI protection, the characteristics of effector differentiated cells within the tissue remains underexplored. In this study, we delve into the nature of TI in splenic myeloid cells, both recruited and local, responsible for tissue mediated protection. Our findings emphasize the centrality of the JAK-STAT1 pathway, activated by the presence of BCG in peripheral immune tissues, in driving TI. Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealed both early and late classical and non-classical monocyte subsets with time-dependent, STAT1-specific signatures. Tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both a pool of tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Lastly, upon transient application of specific JAK-STAT inhibitors acting upstream of STAT1 activation, we were able to pinpoint a pivotal temporal window soon after BCG vaccination that anticipates the onset of training; the interference of which obstructs the TI phenotype. As a whole, our study unravels the diverse manifestations of TI as it emerges in mature immune cells, demonstrating its role within the functional tissue milieu of the spleen.
2025-01-06 | GSE252009 | GEO
Project description:Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow progenitors are well-established mechanisms underpinning durable TI protection, the characteristics of effector differentiated cells within the tissue remains underexplored. In this study, we delve into the nature of TI in splenic myeloid cells, both recruited and local, responsible for tissue mediated protection. Our findings emphasize the centrality of the JAK-STAT1 pathway, activated by the presence of BCG in peripheral immune tissues, in driving TI. Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealed both early and late classical and non-classical monocyte subsets with time-dependent, STAT1-specific signatures. Tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both a pool of tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Lastly, upon transient application of specific JAK-STAT inhibitors acting upstream of STAT1 activation, we were able to pinpoint a pivotal temporal window soon after BCG vaccination that anticipates the onset of training; the interference of which obstructs the TI phenotype. As a whole, our study unravels the diverse manifestations of TI as it emerges in mature immune cells, demonstrating its role within the functional tissue milieu of the spleen.
2025-01-06 | GSE252012 | GEO
Project description:Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow progenitors are well-established mechanisms underpinning durable TI protection, the characteristics of effector differentiated cells within the tissue remains underexplored. In this study, we delve into the nature of TI in splenic myeloid cells, both recruited and local, responsible for tissue mediated protection. Our findings emphasize the centrality of the JAK-STAT1 pathway, activated by the presence of BCG in peripheral immune tissues, in driving TI. Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealed both early and late classical and non-classical monocyte subsets with time-dependent, STAT1-specific signatures. Tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both a pool of tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Lastly, upon transient application of specific JAK-STAT inhibitors acting upstream of STAT1 activation, we were able to pinpoint a pivotal temporal window soon after BCG vaccination that anticipates the onset of training; the interference of which obstructs the TI phenotype. As a whole, our study unravels the diverse manifestations of TI as it emerges in mature immune cells, demonstrating its role within the functional tissue milieu of the spleen.
2025-01-06 | GSE252011 | GEO
Project description:Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow progenitors are well-established mechanisms underpinning durable TI protection, the characteristics of effector differentiated cells within the tissue remains underexplored. In this study, we delve into the nature of TI in splenic myeloid cells, both recruited and local, responsible for tissue mediated protection. Our findings emphasize the centrality of the JAK-STAT1 pathway, activated by the presence of BCG in peripheral immune tissues, in driving TI. Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealed both early and late classical and non-classical monocyte subsets with time-dependent, STAT1-specific signatures. Tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both a pool of tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Lastly, upon transient application of specific JAK-STAT inhibitors acting upstream of STAT1 activation, we were able to pinpoint a pivotal temporal window soon after BCG vaccination that anticipates the onset of training; the interference of which obstructs the TI phenotype. As a whole, our study unravels the diverse manifestations of TI as it emerges in mature immune cells, demonstrating its role within the functional tissue milieu of the spleen.
2025-01-06 | GSE252010 | GEO
Project description:Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow progenitors are well-established mechanisms underpinning durable TI protection, the characteristics of effector differentiated cells within the tissue remains underexplored. In this study, we delve into the nature of TI in splenic myeloid cells, both recruited and local, responsible for tissue mediated protection. Our findings emphasize the centrality of the JAK-STAT1 pathway, activated by the presence of BCG in peripheral immune tissues, in driving TI. Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealed both early and late classical and non-classical monocyte subsets with time-dependent, STAT1-specific signatures. Tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both a pool of tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Lastly, upon transient application of specific JAK-STAT inhibitors acting upstream of STAT1 activation, we were able to pinpoint a pivotal temporal window soon after BCG vaccination that anticipates the onset of training; the interference of which obstructs the TI phenotype. As a whole, our study unravels the diverse manifestations of TI as it emerges in mature immune cells, demonstrating its role within the functional tissue milieu of the spleen.
2025-01-06 | GSE252013 | GEO
Project description:Reprogramming of metabolic pathways in monocytes and macrophages can induce a proatherosclerotic inflammatory memory called trained innate immunity. Here, we have analyzed the role of the Liver X receptor (LXR), a crucial regulator of metabolism and inflammation, in oxidized low-density lipoprotein (oxLDL)-induced trained innate immunity. Human monocytes were incubated with LXR agonists, antagonists, and oxLDL for 24 h. After five days of resting time, cells were restimulated with the TLR-2 agonist Pam3cys. OxLDL priming induced the expression of LXRα but not LXRβ. Pharmacologic LXR activation was enhanced, while LXR inhibition prevented the oxLDL-induced inflammatory response. Furthermore, LXR inhibition blocked the metabolic changes necessary for epigenetic reprogramming associated with trained immunity. In fact, enrichment of activating histone marks at the IL-6 and TNFα promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXRα and LXRβ genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXRα blocked the oxLDL-induced inflammatory response, while knock-down of LXRβ had no effect. We demonstrate a specific and novel role of the LXRα isoform in the regulation of oxLDL-induced trained immunity. Our data reveal important aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation.
| S-EPMC9181299 | biostudies-literature
Project description:IFNs, which transduce pivotal signals through Stat1 and Stat2, effectively suppress the replication of Legionella pneumophila in primary murine macrophages. Although the ability of IFN-γ to impede L. pneumophila growth is fully dependent on Stat1, IFN-αβ unexpectedly suppresses L. pneumophila growth in both Stat1- and Stat2-deficient macrophages. New studies demonstrating that the robust response to IFN-αβ is lost in Stat1-Stat2 double-knockout macrophages suggest that Stat1 and Stat2 are functionally redundant in their ability to direct an innate response toward L. pneumophila. Because the ability of IFN-αβ to signal through Stat1-dependent complexes (i.e., Stat1-Stat1 and Stat1-Stat2 dimers) has been well characterized, the current studies focus on how Stat2 is able to direct a potent response to IFN-αβ in the absence of Stat1. These studies reveal that IFN-αβ is able to drive the formation of a Stat2 and IFN regulatory factor 9 complex that drives the expression of a subset of IFN-stimulated genes, but with substantially delayed kinetics. These observations raise the possibility that this pathway evolved in response to microbes that have devised strategies to subvert Stat1-dependent responses.
| S-EPMC4617678 | biostudies-literature
Project description:Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, BCG (bacillus Calmette-Guerin), and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets. Graphic Abstract: A graphic abstract is available for this article.
| S-EPMC7904591 | biostudies-literature
Project description:Interferon-tau is a maternal recognition factor in ruminant species, and spleen plays an essential role in regulating innate and adaptive immune responses. However, it is not fully understood that early pregnancy induces expression of interferon stimulated genes (ISGs) in the spleen during early pregnancy in ewes. In this study, spleens were collected from ewes at day 16 of the estrous cycle, and on days 13, 16, and 25 of gestation (n = 6 for each group), and RT-qPCR, western blot and immunohistochemistry analysis were used to detect the expression of signal transducer and activator of transcription 1 (STAT1), 2',5'-oligoadenylate synthetase 1 (OAS1), myxovirusresistance protein 1 (Mx1) and C-X-C motif chemokine 10 (CXCL10). The results revealed that STAT1, OAS1 and CXCL10 mRNA and proteins were upregulated in the spleens during early pregnancy, and STAT1 protein was located in connective tissue cells in the capsule and trabeculae, and blood cells and lymphocytes in the red pulp. However, early pregnancy had no significant effects on expression of MX1 mRNA and protein. In conclusion, early pregnancy induces expression of STAT1, OAS1 and CXCL10 in maternal spleen, suggesting that maternal spleen is involved in immune regulation of pregnancy in sheep.
| S-EPMC6912697 | biostudies-literature
Project description:Trained immunity is a de facto memory of innate immune cells, resulting in a long-term increase in innate host defense mechanisms after infection. The long-term heterologous protection conferred by trained immunity is mediated through epigenetic and functional reprogramming of hematopoietic stem and progenitor cells. Because the spleen is a reservoir of undifferentiated monocytes and is considered the prime organ for extramedullary hematopoiesis, we investigated the role of the spleen in the establishment of trained immunity. A β-glucan-induced trained immunity mouse model was performed in previously sham-operated or splenectomized animals. Removal of the spleen did not modulate the proinflammatory cytokine production of in vivo trained peritoneal cells, nor did it ablate the increased percentage of proinflammatory circulatory monocytes and natural killer cells seen in trained animals. However, spleen removal prevented neutrophilia, an important characteristic of trained immunity. These data point to a limited role of the spleen in trained immunity. The pathophysiologic relevance of the spleen in the induction of neutrophilia during trained immunity remains to be fully explored.
| S-EPMC9293451 | biostudies-literature