Similar Datasets
Project description:The immune system is continuously shaped by microorganisms, with viruses emerging as key drivers of immune variability. Gammaherpesviruses (γHVs), including Epstein–Barr virus, have coevolved with their hosts to establish lifelong infections, and may imprint durable innate immune memory. Using Murid herpesvirus 4 in wild-type mice and EBV in humanized models, we show that γHVs remodel monocytes and hematopoietic stem cells at phenotypic, transcriptomic, and epigenetic levels, resulting in altered responses to heterologous challenge. Viral persistence is required for immune priming, and IFN-γ signaling directly reprograms myelopoiesis. During latency, virus-specific resident CD8⁺ T cells accumulate in the bone marrow, and remain poised for rapid IFN-γ release. Upon low-dose LPS stimulation, monocyte-derived IL-27, IL-18, and IL-12 promote bystander IFN-γ secretion from these CD8+ T cells, amplifying myelopoietic rewiring. Thus, γHV latency establishes a cytokine circuit that shapes innate immune training and defines a new equilibrium between host and persistent viruses.
2026-03-17 | GSE324568 | GEO
Project description:The immune system is continuously shaped by microorganisms, with viruses emerging as key drivers of immune variability. Gammaherpesviruses (γHVs), including Epstein–Barr virus, have coevolved with their hosts to establish lifelong infections, and may imprint durable innate immune memory. Using Murid herpesvirus 4 in wild-type mice and EBV in humanized models, we show that γHVs remodel monocytes and hematopoietic stem cells at phenotypic, transcriptomic, and epigenetic levels, resulting in altered responses to heterologous challenge. Viral persistence is required for immune priming, and IFN-γ signaling directly reprograms myelopoiesis. During latency, virus-specific resident CD8⁺ T cells accumulate in the bone marrow, and remain poised for rapid IFN-γ release. Upon low-dose LPS stimulation, monocyte-derived IL-27, IL-18, and IL-12 promote bystander IFN-γ secretion from these CD8+ T cells, amplifying myelopoietic rewiring. Thus, γHV latency establishes a cytokine circuit that shapes innate immune training and defines a new equilibrium between host and persistent viruses.
2026-03-17 | GSE324551 | GEO
Project description:The immune system is continuously shaped by microorganisms, with viruses emerging as key drivers of immune variability. Gammaherpesviruses (γHVs), including Epstein–Barr virus, have coevolved with their hosts to establish lifelong infections, and may imprint durable innate immune memory. Using Murid herpesvirus 4 in wild-type mice and EBV in humanized models, we show that γHVs remodel monocytes and hematopoietic stem cells at phenotypic, transcriptomic, and epigenetic levels, resulting in altered responses to heterologous challenge. Viral persistence is required for immune priming, and IFN-γ signaling directly reprograms myelopoiesis. During latency, virus-specific resident CD8⁺ T cells accumulate in the bone marrow, and remain poised for rapid IFN-γ release. Upon low-dose LPS stimulation, monocyte-derived IL-27, IL-18, and IL-12 promote bystander IFN-γ secretion from these CD8+ T cells, amplifying myelopoietic rewiring. Thus, γHV latency establishes a cytokine circuit that shapes innate immune training and defines a new equilibrium between host and persistent viruses.
2026-03-17 | GSE324569 | GEO
Project description:The immune system is continuously shaped by microorganisms, with viruses emerging as key drivers of immune variability. Gammaherpesviruses (γHVs), including Epstein–Barr virus, have coevolved with their hosts to establish lifelong infections, and may imprint durable innate immune memory. Using Murid herpesvirus 4 in wild-type mice and EBV in humanized models, we show that γHVs remodel monocytes and hematopoietic stem cells at phenotypic, transcriptomic, and epigenetic levels, resulting in altered responses to heterologous challenge. Viral persistence is required for immune priming, and IFN-γ signaling directly reprograms myelopoiesis. During latency, virus-specific resident CD8⁺ T cells accumulate in the bone marrow, and remain poised for rapid IFN-γ release. Upon low-dose LPS stimulation, monocyte-derived IL-27, IL-18, and IL-12 promote bystander IFN-γ secretion from these CD8+ T cells, amplifying myelopoietic rewiring. Thus, γHV latency establishes a cytokine circuit that shapes innate immune training and defines a new equilibrium between host and persistent viruses.
2026-03-17 | GSE324548 | GEO
Project description:ObjectiveTissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride catabolism, is expressed by macrophages in atherosclerotic plaques. We questioned whether LpL, which is also expressed in the bone marrow (BM), affects circulating white blood cells and BM proliferation and modulates macrophage retention within the artery.Approach and resultsWe characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/Ghi). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, which are required for monocyte and monocyte precursor proliferation and differentiation. As a result, differentiation of macrophages from BM-derived monocyte progenitors and monocytes was decreased in MCKL0 mice. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF-macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor in BM-derived macrophage precursor cells. Arterial macrophage numbers decreased after heparin-mediated LpL cell dissociation and by genetic knockout of arterial LpL. Reconstitution of LpL-expressing BM replenished aortic macrophage density.ConclusionsLpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation.
| S-EPMC5823779 | biostudies-literature
Project description:Modest response rates to immunotherapy observed in advanced lung cancer patients underscore the need to identify reliable biomarkers and targets, enhancing both treatment decision-making and efficacy. Factors such as PD-L1 expression, tumor mutation burden, and a 'hot' tumor microenvironment with heightened effector T cell infiltration have consistently been associated with positive responses. In contrast, the predictive role of the abundantly present tumor-infiltrating myeloid cell (TIMs) fraction remains somewhat uncertain, partly explained by their towering variety in terms of ontogeny, phenotype, location, and function. Nevertheless, numerous preclinical and clinical studies established a clear link between lung cancer progression and alterations in intra- and extramedullary hematopoiesis, leading to emergency myelopoiesis at the expense of megakaryocyte/erythroid and lymphoid differentiation. These observations affirm that a continuous crosstalk between solid cancers such as lung cancer and the bone marrow niche (BMN) must take place. However, the BMN, encompassing hematopoietic stem and progenitor cells, differentiated immune and stromal cells, remains inadequately explored in solid cancer patients. Subsequently, no clear consensus has been reached on the exact breadth of tumor installed hematopoiesis perturbing cues nor their predictive power for immunotherapy. As the current era of single-cell omics is reshaping our understanding of the hematopoietic process and the subcluster landscape of lung TIMs, we aim to present an updated overview of the hierarchical differentiation process of TIMs within the BMN of solid cancer bearing subjects. Our comprehensive overview underscores that lung cancer should be regarded as a systemic disease in which the cues governing the lung tumor-BMN crosstalk might bolster the definition of new biomarkers and druggable targets, potentially mitigating the high attrition rate of leading immunotherapies for NSCLC.
| S-EPMC11324509 | biostudies-literature
Project description:Infection is able to elicit innate immunological memory by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. The infection experience is imprinted in the bone marrow (BM) stromal cells, in the form of a constitutive upregulation of the tissue inhibitor of metalloproteinases 1 (TIMP1). TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of Notch which in turn suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis post infection. Thus, our data reveal that infection could establish an inflammatory memory in the BM niche to support a long-term enhanced output of innate immune cells.
2022-06-15 | GSE205728 | GEO
Project description:BackgroundDiabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production.MethodsIn 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling.ResultsIn diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12, a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (Cdh5Cre Egfrfl/fl). We found enhanced HSPC proliferation and increased myeloid cell production in Cdh5Cre Egfrfl/fl mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5Cre Egfrfl/fl mice, significantly delaying wound closure. Atherosclerosis was accelerated in Cdh5Cre Egfrfl/fl mice, leading to larger and more inflamed atherosclerotic lesions in the aorta.ConclusionsIn diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.
| S-EPMC7375017 | biostudies-literature
Project description:Chronic alcohol drinking rewires circulating monocytes and tissue-resident macrophages towards heightened inflammatory states with compromised anti-microbial defenses. As these effects remain consistent in short-lived monocytes after a 1-month abstinence period it is unclear whether these changes are restricted to the periphery or mediated through alterations in the progenitor niche. To test this hypothesis, we profiled monocytes/macrophages and hematopoietic stem cell progenitors (HSCP) of the bone marrow compartment from rhesus macaques after 12 months of ethanol consumption using a combination of functional assays and single cell genomics. Bone marrow-resident monocytes/macrophages from ethanol-consuming animals exhibited heightened inflammation. Differentiation of HSCP in vitro revealed skewing towards monocytes expressing neutrophil-like markers with heightened inflammatory responses to bacterial agonists. Single cell transcriptional analysis of HSCPs showed reduced proliferation but increased inflammatory markers in mature myeloid progenitors. We observed transcriptional signatures associated with increased oxidative and cellular stress as well as oxidative phosphorylation in immature and mature myeloid progenitors. Single cell analysis of the chromatin landscape showed altered drivers of differentiation in monocytes and progenitors. Collectively, these data indicate that chronic ethanol drinking results in remodeling of the transcriptional and epigenetic landscapes of the bone marrow compartment leading to altered functions in the periphery.
| S-EPMC10081177 | biostudies-literature
Project description:Although accumulation of dendritic cell (DC) precursors occurs in bone marrow, the terminal differentiation of these cells takes place outside bone marrow. The signaling, regulating this process, remains poorly understood. We demonstrated that this process could be differentially regulated by Notch ligands: Jagged-1 (Jag1) and Delta-like ligand 1 (Dll1). In contrast to Dll1, Jag1, in vitro and during induced myelopoiesis in vivo, prevented DC differentiation by promoting the accumulation of their precursors. Although both ligands activated Notch in hematopoietic progenitor cells, they had an opposite effect on Wnt signaling. Dll1 activated Wnt pathways, whereas Jag1 inhibited it via downregulation of the expression of the Wnt receptors Frizzled (Fzd). Jag1 suppressed fzd expression by retaining histone deacetylase 1 in the complex with the transcription factor CSL/CBF-1 on the fzd promoter. Our results suggest that DC differentiation, during induced myelopoiesis, can be regulated by the nature of the Notch ligand expressed on adjacent stroma cells.
| S-EPMC3787311 | biostudies-literature