The murine transcriptome reveals global aging nodes with organ-specific phase and amplitude

2019 ◽  
Author(s):  
Nicholas Schaum ◽  
Benoit Lehallier ◽  
Oliver Hahn ◽  
Shayan Hosseinzadeh ◽  
Song E. Lee ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Mitochondrial Function ◽  
Cell Activation ◽  
Plasma Cells ◽  
Immune Cell ◽  
Age Of Onset ◽  
Systemic Circulation ◽  
Protein Levels ◽  
Organ Specific ◽  
Highly Correlated

Aging is the single greatest cause of disease and death worldwide, and so understanding the associated processes could vastly improve quality of life. While the field has identified major categories of aging damage such as altered intercellular communication, loss of proteostasis, and eroded mitochondrial function1, these deleterious processes interact with extraordinary complexity within and between organs. Yet, a comprehensive analysis of aging dynamics organism-wide is lacking. Here we performed RNA-sequencing of 17 organs and plasma proteomics at 10 ages across the mouse lifespan. We uncover previously unknown linear and non-linear expression shifts during aging, which cluster in strikingly consistent trajectory groups with coherent biological functions, including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Remarkably, these gene sets are expressed similarly across tissues, differing merely in age of onset and amplitude. Especially pronounced is widespread immune cell activation, detectable first in white adipose depots in middle age. Single-cell RNA-sequencing confirms the accumulation of adipose T and B cells, including immunoglobulin J-expressing plasma cells, which also accrue concurrently across diverse organs. Finally, we show how expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to aging of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of aging, thereby providing a foundation to track systemic sources of declining health at old age.

scholarly journals POS1223 RAS GUANYL RELEASING PROTEIN 1 (RASGRP1) IN PERIPHERAL B CELLS LINKS RA TO COVID-19

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 895.2-895
Author(s):  
S. Hannawi ◽  
F. Alqutami ◽  
M. Y. Hachim
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Immune Cell ◽  
In Silico Analysis ◽  
Differentially Expressed ◽  
Transcriptional Enhancer ◽  
Activated T Cells

Background:Changes in the B cell subpopulations is a hallmark of the antiviral response against SARS-CoV-2 and is associated with COVID-19 severity (1). Recently our group showed common derangement observed in rheumatoid arthritis (RA) and COVID-19 (2). In RA, synovium attracts potentially autoreactive—B cells and plasma cells that play a central role in RA pathogenesis (3). We were interested to know the similarity in B cell’s transcriptomic changes specific to RA and COVID-19.Objectives:Identify similar upregulated genes in synovium and B cells in RA and at the same time are differentially expressed in B cells infected with SARS-CoV-2 or from COVID-19 patients.Methods:RNAseq dataset (GSE89408) of (218) samples isolated from joint synovial biopsies from subjects with and without rheumatoid arthritis were retrieved from GEO online database. Differentially expressed genes (DRGs) specific to RA were identified after exclusion of those upregulated in Osteoarthritis or other joint condition samples in the same dataset. The RA specific genes were intersected with DEGs between B cells from healthy versus RA as extracted from (GSE110999) dataset. The shortlisted genes specifically upregulated in B cells of RA were identified and were explored in B cells COVID-19 transcriptome datasets using (https://metascape.org/COVID).Results:60 genes were found to be specifically upregulated in RA synovium and B cells and are changed in B cells infected with SARS-CoV-2 or from COVID-19 patients, Figure (1-A). Those genes were involved in interferon signaling, antiviral and immune cell activation. RASGRP1 was common between B cells of RA and COVID-19 and might play a role in the pathogenesis of both, Figure (1-B). RASGRP1 controls ERK/MAPK kinase cascade needed in B-/T-cell differentiation and development. It is vital to protect against viral infection and the autoimmune associated proliferation of activated T-cells like RA (4). We checked its level in another dataset (GSE152641) of the whole blood RNASeq of 62 COVID-19 patients and 24 healthy controls. RASGRP1 was significantly down in COVID-19 compared to healthy control, Figure (1-C).Conclusion:SARS-CoV-2 impair B and T’s cells’ immune response through its action on RASGRP1 and that can be a novel mechanistic explanation of how the virus decreases immune cells and impair the B cell’s humoral immunity.References:[1]Sosa-Hernández VA, Torres-Ruíz J, Cervantes-Díaz R, Romero-Ramírez S, Páez-Franco JC, Meza-Sánchez DE, et al. B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients. Frontiers in Immunology. 2020;11(3244).[2]Hachim MY, Hachim IY, Naeem KB, Hannawi H, Al Salmi I, Hannawi S. C-C chemokine receptor type 5 links COVID-19, rheumatoid arthritis, and Hydroxychloroquine: in silico analysis. Translational Medicine Communications. 2020;5(1):14.[3]Doorenspleet ME, Klarenbeek PL, de Hair MJ, van Schaik BD, Esveldt RE, van Kampen AH, et al. Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity. Ann Rheum Dis. 2014;73(4):756-62.[4]Molineros JE, Singh B, Terao C, Okada Y, Kaplan J, McDaniel B, et al. Mechanistic Characterization of RASGRP1 Variants Identifies an hnRNP-K-Regulated Transcriptional Enhancer Contributing to SLE Susceptibility. Frontiers in Immunology. 2019;10(1066).Disclosure of Interests:None declared

scholarly journals Identification of Galectin-3 as Potential Biomarkers for Renal Fibrosis by RNA-Sequencing and Clinicopathologic Findings of Kidney Biopsy

2021 ◽  
Vol 8 ◽  
Author(s):  
Shuo-Ming Ou ◽  
Ming-Tsun Tsai ◽  
Huan-Yuan Chen ◽  
Fu-An Li ◽  
Wei-Cheng Tseng ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Renal Fibrosis ◽  
Cell Activation ◽  
Kidney Biopsy ◽  
Immune Cell ◽  
Interstitial Fibrosis ◽  
Sequencing Analysis ◽  
Tubular Atrophy ◽  
Renal Histology ◽  
Galectin 3

Background: Galectin-3 (Gal-3) is a multifunctional glycan-binding protein shown to be linked to chronic inflammation and fibrogenesis. Plasma Gal-3 is associated with proteinuria and renal dysfunction, but its role has never been confirmed with kidney biopsy results. In our study, we aimed to explore the expression of Gal-3 in biopsy-proven patients, and we tested the hypothesis that chronic kidney disease (CKD) leads to upregulation of plasma Gal-3 expression in corresponding biopsy findings and RNA sequencing analysis.Method: In 249 patients (male/female: 155/94, age: 57.2 ± 16.3 years) who underwent kidney biopsy, plasma levels of Gal-3 were measured to estimate the association of renal fibrosis. Relationships between plasma Gal-3 levels, estimated glomerular filtration rate (eGFR) and renal histology findings were also assessed. We further examined the gene expression of Gal-3 in RNA-sequencing analysis in biopsy-proven patients.Results: Compared to patients without CKD, CKD patients had higher levels of plasma Gal-3 (1,016.3 ± 628.1 pg/mL vs. 811.6 ± 369.6 pg/ml; P = 0.010). Plasma Gal-3 was inversely correlated with eGFR (P = 0.005) but not with proteinuria. Higher Gal-3 levels were associated with interstitial fibrosis, tubular atrophy and vascular intimal fibrosis. RNA-sequencing analysis showed the upregulation of Gal-3 in fibrotic kidney biopsy samples, and the differentially expressed genes were mainly enhanced in immune cell activation and the regulation of cell-cell adhesion.Conclusions: Plasma Gal-3 levels are inverse correlated with eGFR but positively correlated with renal fibrosis, which may be involved in the immune response and associated pathways. These findings support the role of Gal-3 as a predictive marker of renal fibrosis.

scholarly journals Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes

Circulation ◽  
2021 ◽  
Author(s):  
Sabrina Geisberger ◽  
Hendrik Bartolomaeus ◽  
Patrick Neubert ◽  
Ralf Willebrand ◽  
Christin Zasada ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Cell Activation ◽  
Immune Cell ◽  
Mononuclear Phagocytes ◽  
Plasma Sodium ◽  
T Cell Migration ◽  
Single Meal ◽  
And Function ◽  
Extracellular Sodium

Background: Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially, but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional and functional adaption of human and murine mononuclear phagocytes (MNP). Methods: Using Seahorse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays we characterize the central carbon metabolism and mitochondrial function of human and murine MNP under HS in vitro . HS as well as pharmacologic uncoupling of the electron transport chain (ETC) under normal salt (NS) is used to analyze mitochondrial function on immune cell activation and function (as determined by E.coli killing and CD4 + T cell migration capacity). In two independent clinical studies we analyze the impact of a HS diet over two weeks (NCT02509962) and short-term salt challenge by a single meal (NCT04175249) on mitochondrial function of human monocytes in vivo . Results: Extracellular sodium was taken up into the intracellular compartment followed by the inhibition of mitochondrial respiration in murine and human macrophages (MΦ). Mechanistically, HS reduces mitochondrial membrane potential, ETC complex II activity, oxygen consumption, and ATP production independently of the polarization status of MΦ. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like MΦ and diminished CD4+ T cell migration in HS-treated M2-like MΦ. Pharmacologic uncoupling of the ETC under NS phenocopies HS-induced transcriptional changes and bactericidal function of human and murine MNP. Clinically, also in vivo rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both, a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of ̃x = 2 mM and ̃x = 2.3 mM , respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. Conclusions: Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. While these functional changes might help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory CVD.

scholarly journals Systems analysis of protective immune responses to RTS,S malaria vaccination in humans

2017 ◽  
Vol 114 (9) ◽  
pp. 2425-2430 ◽  
Author(s):  
Dmitri Kazmin ◽  
Helder I. Nakaya ◽  
Eva K. Lee ◽  
Matthew J. Johnson ◽  
Robbert van der Most ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Nk Cell ◽  
Circumsporozoite Protein ◽  
Dendritic Cell Activation ◽  
Antibody Titers ◽  
Malaria Vaccine Candidate ◽  
Highly Correlated

RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4+ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.

Abstract 60: The Role of Mononuclear Phagocytes in Pressure Overload Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Bindiya Patel ◽  
Mohamed Ismahil ◽  
Mehak Goel ◽  
Tariq Hamid ◽  
Shyam Bansal ◽  
...  
Keyword(s):  
Cell Activation ◽  
Inflammatory Cell ◽  
Immune Cell ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Systemic Circulation ◽  
Compensatory Hypertrophy ◽  
Mononuclear Phagocytes ◽  
Cell Profile

We previously reported that chronic ischemic HF induced by coronary ligation results in an exacerbated pro-inflammatory cell profile in the systemic circulation, spleen, and failing heart. In addition, this pro-inflammatory cell profile was strongly influenced by the cardiosplenic axis; however, the role of this axis in other etiologies of HF is unknown. Immune cells infiltrate the heart early (1-4 weeks) after pressure-overload injury, but it is unknown whether these cells persist and are of pathological import during chronic pressure-overload HF. We hypothesized that phenotypic changes in mononuclear phagocytes are necessary for the transition from compensatory hypertrophy to chronic HF during sustained pressure-overload, and that inhibition of myocardial immune cell infiltration would ameliorate this progression. Pressure-overload was induced by transverse aortic constriction (TAC) in wild-type (WT) C57BL/6 mice, and in macrophage Fas-induced apoptosis (MAFIA) Tg mice, which allows ablation of c-fms expressing cells upon administration of the AP20187 dimerizer. Compared to sham mice, TAC mice developed progressive cardiac dysfunction beginning at 2 w with significantly (p<0.05) reduced LVEF (59 ± 10 vs 67 ± 3 %), increased left atrial size (2.29 ± 0.1 vs 2.04 ± 0.1 mm), and increased E/E’ Doppler ratio (31.8 ± 6 vs 24.0 ± 3). Circulating CD11b+Lineage- monocytes were elevated in TAC mice at 2 w (1.7 ± 0.2 vs 1.0 ± 0.1 %, p<0.05); however, these levels normalized by 8 w. Moreover, at 8 w, no significant differences in the levels of splenic and cardiac mononuclear phagocytes were seen between TAC and sham mice. Systemic ablation of mononuclear phagocytes beginning 2 w after TAC in MAFIA AP20187-treated mice did not rescue cardiac function or delay HF progression compared to TAC MAFIA vehicle-treated mice over the course of 16 w (LVEF 43 ± 18 vs 45 ± 18 %). We conclude that in contrast to chronic ischemic HF, inflammatory cell-mediated cardiac injury does not have primacy in chronic non-ischemic HF induced by pressure-overload. These findings highlight the importance of the index injury in regard to immune cell activation in HF, and suggest that therapeutic immunomodulatory approaches may not be equivalent across the various etiologies of this disease.

scholarly journals A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

2021 ◽  
Author(s):  
Elo Madissoon ◽  
Amanda Jane Oliver ◽  
Vitalii Kleshchevnikov ◽  
Anna Wilbrey-Clark ◽  
Krzysztof Polanski ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Plasma Cells ◽  
Immune Cell ◽  
Human Lung ◽  
Interaction Analysis ◽  
Cell Types ◽  
Cell Interaction ◽  
Data Set ◽  
Duct Cells

Multiple distinct cell types of the human lung and airways have been defined by single cell RNA sequencing (scRNAseq). Here we present a multi-omics spatial lung atlas to define additional heterogeneity and novel cell types which we map back into the macro- and micro-anatomical tissue context to define functional tissue microenvironments. First, we have generated a single cell and nuclei RNA sequencing, VDJ-sequencing and Visium Spatial Transcriptomics data set from 5 different locations of the human lung and airways. Second, we define additional cell types/states, as well as spatially map novel and known human airway cell types, such as chondrocytes, submucosal gland (SMG) duct cells, distinct pericyte and smooth muscle subtypes, immune-recruiting fibroblasts, peribronchial and perichondrial fibroblasts, peripheral nerve associated fibroblasts and Schwann cells. Finally, we define a survival niche for IgA-secreting plasma cells at the SMG, comprising the newly defined epithelial SMG-Duct cells, and B and T lineage immune cells. Using our transcriptomic data for cell-cell interaction analysis, we propose a signalling circuit that establishes and supports this niche. Overall, we provide a transcriptional and spatial lung atlas with multiple novel cell types that allows for the study of specific tissue microenvironments such as the newly defined gland-associated lymphoid niche (GALN).

scholarly journals CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load and TP53 mutations

2020 ◽  
Author(s):  
Andrew M. Leader ◽  
John A. Grout ◽  
Christie Chang ◽  
Barbara Maier ◽  
Alexandra Tabachnikova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Antigen ◽  
Cell Activation ◽  
Plasma Cells ◽  
Immune Cell ◽  
Early Stage ◽  
Driver Mutations ◽  
Activated T Cells ◽  
Cell Content ◽  
Immune Cell Activation

SUMMARYImmunotherapy is becoming a mainstay in the treatment of NSCLC. While tumor mutational burden (TMB) has been shown to correlate with response to immunotherapy, little is known about the relation of the baseline immune response with the tumor genotype. Here, we profiled 35 early stage NSCLC lesions using multiscale single cell sequencing. Unsupervised clustering identified in a subset of patients a key cellular module consisting of PDCD1+ CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). Transcriptional data from two NSCLC cohorts confirmed a subset of patients with LCAMhi enrichment, which was independent of overall immune cell content. The LCAMhi module strongly correlated with TMB, expression of cancer testis antigens, and with TP53 mutations in smokers and non-smokers. These data establish LCAM as a key mode of immune cell activation associated with high tumor antigen load and driver mutations.

scholarly journals Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yuka Takemon ◽  
Joel M Chick ◽  
Isabela Gerdes Gyuricza ◽  
Daniel A Skelly ◽  
Olivier Devuyst ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Aging Process ◽  
Biological Processes ◽  
Age Changes ◽  
Molecular Changes ◽  
Protein Levels ◽  
Age Related ◽  
Organ Specific ◽  
Incomplete Picture ◽  
Age Related Changes

Little is known about the molecular changes that take place in the kidney during the aging process. In order to better understand these changes, we measured mRNA and protein levels in genetically diverse mice at different ages. We observed distinctive change in mRNA and protein levels as a function of age. Changes in both mRNA and protein are associated with increased immune infiltration and decreases in mitochondrial function. Proteins show a greater extent of change and reveal changes in a wide array of biological processes including unique, organ-specific features of aging in kidney. Most importantly, we observed functionally important age-related changes in protein that occur in the absence of corresponding changes in mRNA. Our findings suggest that mRNA profiling alone provides an incomplete picture of molecular aging in the kidney and that examination of changes in proteins is essential to understand aging processes that are not transcriptionally regulated.

scholarly journals Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis

2021 ◽  
Vol 118 (33) ◽  
pp. e2023216118
Author(s):  
Zhaohao Huang ◽  
Binyao Chen ◽  
Xiuxing Liu ◽  
He Li ◽  
Lihui Xie ◽  
...  
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Cell Activation ◽  
Plasma Cells ◽  
Immune Cell ◽  
Cell Communication ◽  
Lower Percentage ◽  
Human Immune System ◽  
Communication Analysis ◽  
The Impact

Sex and aging influence the human immune system, resulting in disparate responses to infection, autoimmunity, and cancer. However, the impact of sex and aging on the immune system is not yet fully elucidated. Using small conditional RNA sequencing, we found that females had a lower percentage of natural killer (NK) cells and a higher percentage of plasma cells in peripheral blood compared with males. Bioinformatics revealed that young females exhibited an overrepresentation of pathways that relate to T and B cell activation. Moreover, cell–cell communication analysis revealed evidence of increased activity of the BAFF/APRIL systems in females. Notably, aging increased the percentage of monocytes and reduced the percentage of naïve T cells in the blood and the number of differentially expressed genes between the sexes. Aged males expressed higher levels of inflammatory genes. Collectively, the results suggest that females have more plasma cells in the circulation and a stronger BAFF/APRIL system, which is consistent with a stronger adaptive immune response. In contrast, males have a higher percentage of NK cells in blood and a higher expression of certain proinflammatory genes. Overall, this work expands our knowledge of sex differences in the immune system in humans.

Oxidized Haemoglobin–Driven Endothelial Dysfunction and Immune Cell Activation: Novel Therapeutic Targets for Atherosclerosis

2013 ◽  
Vol 20 (37) ◽  
pp. 4806-4814 ◽  
Author(s):  
Brigitta Buttari ◽  
Elisabetta Profumo ◽  
Rita Businaro ◽  
Luciano Saso ◽  
Raffaele Capoano ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Cell Activation ◽  
Immune Cell ◽  
Therapeutic Targets ◽  
Immune Cell Activation ◽  
Novel Therapeutic
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