Human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE94499 | GEO | 2017/07/26
SECONDARY ACCESSION(S): PRJNA369858
REPOSITORIES: GEO
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Project description:Age-related alterations in immunity have been linked to increased incidence of infections and decreased responses to vaccines in the aging population. Human peripheral blood monocytes are known to promote Ag presentation and antiviral activities; however, the impact of aging on monocyte functions remains an open question. We present an in-depth global analysis examining the impact of aging on classical (CD14+CD16-), intermediate (CD14+CD16+), and nonclassical (CD14dimCD16+) monocytes. Monocytes sorted from nonfrail healthy adults (21-40 y) and old (?65 y) individuals were analyzed after stimulation with TLR4, TLR7/8, and retinoic acid-inducible gene I agonists. Our data showed that under nonstimulated conditions, monocyte subsets did not reveal significant age-related alternations; however, agonist stimulated-monocytes from adults and old subjects did show differences at the transcriptional and functional levels. These alternations in many immune-related transcripts and biological processes resulted in reduced production of IFN-?, IFN-?, IL-1?, CCL20, and CCL8, and higher expression of CX3CR1 in monocytes from old subjects. Our findings represent a comprehensive analysis of the influence of human aging on pattern recognition receptors signaling and monocyte functions, and have implications for strategies to enhance the immune response in the context of infection and immunization.
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Project description:Age-related alterations in immunity have been linked to increased incidence of infections and decreased responses to vaccines in the aging population. Human peripheral blood monocytes are known to promote antigen presentation and antiviral activities; however, the impact of aging on monocyte functions remains an open question. We present an in-depth global analysis examining the impact of aging on classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14dimCD16+) monocytes. Monocytes sorted from non-frail healthy adults (18-40 yrs) and old (≥ 65 yrs) individuals were analyzed after stimulation with TLR4, TLR7/8, and RIG-I agonists. Our data showed under non-stimulated conditions, monocyte subsets did not reveal significant age-related alternations; however, agonist stimulated-monocytes from adults and old subjects did show differences at the transcriptional and functional levels. These alternations in many immune-related transcripts and biological processes resulted in reduced production of IFNα, IFN, IL-1β, CCL20, and CCL8, and higher expression of CX3CR1 in monocytes from old subjects. Our findings represent a comprehensive analysis of the influence of human aging on pattern recognition receptors signaling and monocyte functions, and have implications for strategies to enhance the immune response in the context of infection and immunization.
2017-07-27 | GSE94497 | GEO
Project description:Age-related alterations in immunity have been linked to increased incidence of infections and decreased responses to vaccines in the aging population. Human peripheral blood monocytes are known to promote antigen presentation and antiviral activities; however, the impact of aging on monocyte functions remains an open question. We present an in-depth global analysis examining the impact of aging on classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14dimCD16+) monocytes. Monocytes sorted from non-frail healthy adults (18-40 yrs) and OLD (≥ 65 yrs) individuals were analyzed after stimulation with TLR4, TLR7/8, and RIG-I agonists. Our data showed under non-stimulated conditions, monocyte subsets did not reveal significant age-related alternations; however, agonist stimulated-monocytes from adults and OLD subjects did show differences at the transcriptional and functional levels. These alternations in many immune-related transcripts and biological processes resulted in reduced production of IFNα, IFN, IL-1β, CCL20, and CCL8, and higher expression of CX3CR1 in monocytes from OLD subjects. Our findings represent a comprehensive analysis of the influence of human aging on pattern recognition receptors signaling and monocyte functions, and have implications for strategies to enhance the immune response in the context of infection and immunization.
2017-07-27 | GSE94496 | GEO
Project description:Human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists
| PRJNA369858 | ENA
Project description:Alveolar macrophages (AMs) are functionally important innate cells involved in lung homeostasis and immunity and whose diversity in health and disease is a subject of intense investigations. Yet, it remains unclear to what extent conditions like smoking or chronic obstructive pulmonary disease (COPD) trigger changes in the AM compartment. Here, we aimed to explore heterogeneity of human AMs isolated from healthy nonsmokers, smokers without COPD, and smokers with COPD by analyzing BAL fluid cells by flow cytometry and bulk and single-cell RNA sequencing. We found that subpopulations of BAL fluid CD206+ macrophages could be distinguished based on their degree of autofluorescence in each subject analyzed. CD206+ autofluorescenthigh AMs were identified as classical, self-proliferative AM, whereas autofluorescentlow AMs were expressing both monocyte and classical AM-related genes, supportive of a monocytic origin. Of note, monocyte-derived autofluorescentlow AMs exhibited a functionally distinct immunoregulatory profile, including the ability to secrete the immunosuppressive cytokine IL-10. Interestingly, single-cell RNA-sequencing analyses showed that transcriptionally distinct clusters of classical and monocyte-derived AM were uniquely enriched in smokers with and without COPD as compared with healthy nonsmokers. Of note, such smoking-associated clusters exhibited gene signatures enriched in detoxification, oxidative stress, and proinflammatory responses. Our study independently confirms previous reports supporting that monocyte-derived macrophages coexist with classical AM in the airways of healthy subjects and patients with COPD and identifies smoking-associated changes in the AM compartment that may favor COPD initiation or progression.
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Project description:Signalling through pattern recognition receptors (PRRs) leads to strong proinflammatory responses, enhancing the activity of antigen presenting cells and shaping adaptive immune responses against tumour associated antigens. Unfortunately, toxicities associated with systemic administration of these agonists have limited their clinical use to date. Direct injection of PRR agonists into the tumour can enhance immune responses by directly modulating the cells present in the tumour microenvironment. This can improve local antitumour activity, but importantly, also facilitates systemic responses that limit tumour growth at distant sites. As such, this form of therapy could be used clinically where metastatic tumour lesions are accessible, or as neoadjuvant therapy. In this review, we summarise current preclinical data on intratumoural administration of PRR agonists, including new strategies to optimise delivery and impact, and combination studies with current and promising new cancer therapies.
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Project description:Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However, transcriptional heterogeneity of human intestinal TRM cells remains undefined. Here, we investigate transcriptional and functional heterogeneity of human TRM cells through study of donor-derived TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We define a transcriptional signature discriminating these populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft, and lymphocytes from healthy gut, confirm these CD8+ TRM phenotypes. CD8+ CD69+CD103+ TRM cells produce interleukin-2 (IL-2) and demonstrate greater polyfunctional cytokine production, whereas β2-integrin+CD69+CD103- TRM cells have higher granzyme expression. Analysis of intestinal CD4+ T cells identifies several parallels, including a β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.
| S-EPMC7816164 | biostudies-literature
Project description:BackgroundIt has been widely accepted that monocytes are one of the central mediators contributing to inflammaging. However, it remains unclear whether aged monocytes, similar to aged T cells, have characteristics of hyperactivation and increased expression of co-inhibitory molecules.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from young (21-40 years old), middle-aged (41-60 years old), and older human subjects (> 60 years old). Flow cytometry was used to monitor changes in the expression of surface molecules of monocyte subsets and cytokine-producing capacity.ResultsWe observed increased tumor necrosis factor-α: TNF-α and decreased interleukin-6 (IL-6) production in monocytes from older adults compared with young and middle-aged adults. Older adults had a greater percentage of intermediate and non-classical monocyte subsets, along with increased levels of the immune activation markers human leukocyte antigen-DR (HLA-DR), and adhesion molecules cluster of differentiation molecule 11b (CD11b) and L-selectin (CD62L). Furthermore, we observed increased C-C motif chemokine receptor 2 (CCR2) expression on classical monocytes and decreased C-X3-C motif chemokine receptor 1 (CX3CR1) expression on non-classical monocytes in older adult subjects. The expression of co-inhibitory receptors was reduced on monocyte subsets in older adults.ConclusionsCirculating monocytes in older adults exhibit increased expression of activation, adhesion, and migration markers, but decreased expression of co-inhibitory molecules.
| S-EPMC9745938 | biostudies-literature
Project description:BackgroundAge-associated changes in immunity are inextricably linked to chronic inflammation and age-related diseases, the impact of aging on monocyte subsets is poorly understood.MethodsFlow cytometry was applied to distinguish three monocyte subsets between 120 young and 103 aged individuals. We then analyzed the expression profiles of three monocyte subsets from 9 young and 9 older donors and CD14+ monocytes from 1202 individuals between 44 and 83 years old. Flow cytometry was used to measure β-galactosidase activities, ROS levels, mitochondrial contents, mitochondrial membrane potentials (MMPs) and intracellular IL-6 levels in three monocyte subsets of young and elderly individuals, and plasma IL-6 levels were detected by electrochemiluminescence immunoassay. Mitochondrial stress and glycolytic rate of CD14+ monocytes from young and aged individuals were measured by Seahorse XFe24 Analyzer.ResultsCompared with young individuals, the percentage of classical subset in aged persons significantly decreased, while the proportion of nonclassical subset increased. Age-related differential genes were obviously enriched in cellular senescence, ROS, oxidative phosphorylation, mitochondrial respiratory chain, IL-6 and ribosome-related pathways. Compared with young individuals, the β-galactosidase activities, ROS contents, intracellular IL-6 levels of three monocyte subsets, and plasma IL-6 levels in aged individuals were significantly elevated, while the MMPs apparently declined with age and the mitochondrial contents were only increased in intermediate and nonclassical subsets. CD14+ monocytes from elderly adults had conspicuously lower basal and spare respiratory capacity and higher basal glycolysis than those from young individuals.ConclusionsDuring aging, monocytes exhibited senescence-associated secretory phenotype, mitochondrial dysfunction, decreased oxidative phosphorylation and increased glycolysis and the nonclassical subset displayed the clearest features of aging. Our study comprehensively investigated age-related transcriptional alterations of three monocyte subsets and identified the pivotal pathways of monocyte senescence, which may have significant implications for tactics to alleviate age-related conditions.
| S-EPMC10523626 | biostudies-literature