Project description:Neutrophils form the most abundant leukocyte subset and are central to many disease processes. Technical challenges in transcriptomic profiling have prohibited genetical genomic approaches to date. Here, we map expression quantitative trait loci (eQTL) in peripheral blood CD16+ neutrophils from 101 healthy European adults. This dataset includes expression data from neutrophils. The genotypes and expression data from monocytes can be found in E-MTAB-2232 - Genetics of gene expression across innate immune stimulation in primary monocytes.
Project description:As innate immune cells, monocytes play a central role in antifungal immunity. Using proteome studies in primary human monocytes, which were stimulated by Candida albicans (yeast) in vitro. Here we describe the changes of proteins in monocytes and demonstrate that in the early stage of infection, the differences of innate immune response triggered by C. albicans over time.
Project description:Monocytes and macrophages are essential cells in the early response in their capacity as ubiquitous phagocytic cells. They phagocytose microorganisms or damaged cells and sense pathogen/damage-associated molecular patterns (PAMPs/DAMPs) through innate receptors such as Toll-like receptors (TLRs). We investigated a phenomenon where co-signaling from TLR2 and TLR8 in human primary monocytes provides a distinct immune activation profile compared to signaling from either TLR alone. Comparison of gene signatures induced by either stimulus alone or together, show that co-signaling result in downstream differences in regulation of signaling and gene transcription. To investigate the interaction of TLR2 and TLR8 stimulation primary human monocytes isolated from buffy coat were stimulated with TLR2/6 ligand FSL-1 and/or TLR7/8 ligand CL075 and the gene expression monitored at 1,2 and 3h post stimulation.
Project description:Innate immune responses vary by pathogen and host genetics. We generated transcriptomes of monocytes from 215 individuals, with and without stimulation (3h or 6h) by fungal, Gram-negative or Gram-positive bacterial pathogens. Monocytes showed a conserved response to bacterial pathogens and a distinct antifungal response. Mapping expression quantitative trait loci (eQTLs) identified 745 response eQTLs (reQTLs) and corresponding genes showing pathogen-specific effects. Compared to all differentially expressed genes, reQTL-regulated genes were more frequently upregulated, indicating cell-activating gene regulation. ReQTL-regulated gene products are essential in NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. ReQTLs functionally characterize risk variants identified through genome-wide association studies for autoimmunity, inflammatory or infectious diseases and cancer. Thus, in addition to the transcriptional response of monocytes, their genetic regulation differs for bacterial and fungal pathogens. ReQTLs help explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.
Project description:In the present study we examined the effect of hepatocyte-derived exosomes (HDE) on innate immune cells by treating a human monocyte cell line (THP-1 cells) with exosomes collected from the culture medium of acetaminophen (APAP)-treated and untreated primary human hepatocytes and comparing the cytokine response to THP-1 cells treated with mock- and medium-controls. We profiled the gene expression changes observed in the HDE-exposed monocytes prior to LPS stimulation. Findings from our research suggest that HDE may be essential for maintaining immune homeostasis.
Project description:Monocytes and macrophages constitute important components of immune system. Monocytes differentiate into macrophages following stimulation with cytokines and/or microbial molecule. Macrophages play central role in the maintenance of tissue homeostasis, development and its restoration after injury, as well as the initiation and resolution of innate and adaptive immunity. Though macrophages were long considered to be derived from differentiation of bone marrow monocytes, recent studies have proved that tissue resident macrophages are derived from yolk sac macrophages, fetal liver macrophages, can self-replicate from local proliferation. However, during homeostatic adaptations, injury and inflammation macrophages of different phenotypes can be recruited from the monocyte reservoirs of blood, spleen and bone marrow. Our studies show that Lysophosphatidic acid (LPA), a small lipid molecule converts monocytes into macrophages. We report the gene expression profile of primary mouse bone marrow monocytes treated for 5 days with LPA with respect to control monocytes.
Project description:Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma, SSc), with increased expression of IFN-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. Recently, we found that EBV is deregulated in SSc with abnormal expression of viral lytic-genes in PBMCs and skin. Since monocytes/macrophages are involved in innate immune recognition of EBV/lytic infection, we sought to determine whether EBV might contribute to their activation in SSc. In this study, using recombinant-EBV we infected monocytes from SSc and healthy donors (HDs), we found that viral replication is essential for inducing the expression of TLR8 in EBV-infected primary monocytes. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were up-regulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally-induced-TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral lytic-mRNA and -proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes.
Project description:In this study we investigated the mechanisms involved in memory T-cell mediated protection using mice vaccinated with the intracellular bacterium Listeria monocytogenes. Our working hypothesis was that rapid activation of cells of the innate immune system, in particular inflammatory Ly6C+ monocytes, were essential in effective protection, in a memory T cell-dependent manner. Thus we generated a comprehensive comparison of the genetic program of activated Ly6C+ monocytes during a primary or a secondary infection with Listeria monocytogenes, at 8 hours post challenge infection. Abstract of corresponding publication: Cells of the innate immune system are essential for host defenses against primary microbial pathogen infections, yet their involvement in effective memory responses of vaccinated individuals has been poorly investigated. Here we show that memory T cells instruct innate cells to become potent effector cells in a systemic and a mucosal model of infection. Memory T cells controlled phagocyte, dendritic cell and NK or NK T cell mobilization and induction of a strong program of differentiation, which included their expression of effector cytokines and microbicidal pathways, all of which were delayed in non-vaccinated hosts. Disruption of IFN-gamma-signaling in Ly6C+ monocytes, dendritic cells and macrophages impaired these processes and the control of pathogen growth. These results reveal how memory T cells, through rapid secretion of IFN-gamma, orchestrate extensive modifications of host innate immune responses that are essential for effective protection of vaccinated hosts. Overall design: Inflammatory monocytes were purified (see below for isolation method) from 4 groups of 3 individual mice each (triplicate): (i) uninfected mice, (ii) primary infected, (iii) secondary infected, (iv) secondary infected and T-cell depleted 1 day before. Isolation of cells was done on 3 different days for true biological replicates.
Project description:Monocytes undergo global gene expression changes upon stimulation, thus a significant proportion of eQTL are specific to activation state. Here we systematically explore determinants of gene and transcript expression in monocytes from 185 individuals in the untreated state and post-exposure to IFNγ or lipopolysaccharide (LPS).