Ageing compromises mouse thymus function and remodels epithelial cell differentiation
- University of Edinburgh, United Kingdom
- Wellcome Sanger Institute, United Kingdom
- University of Oxford, United Kingdom
- University of Basel, and University Children's Hospital, Switzerland
- Chan Zuckerberg Biohub, United States
- Wellcome Trust Sanger Institute, United Kingdom
Abstract
Ageing is characterised by cellular senescence, leading to imbalanced tissue maintenance, cell death and compromised organ function. This is first observed in the thymus, the primary lymphoid organ that generates and selects T cells. However, the molecular and cellular mechanisms underpinning these ageing processes remain unclear. Here, we show that mouse ageing leads to less efficient T cell selection, decreased self-antigen representation and increased T cell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing, we find that progenitor cells are the principal targets of ageing, whereas the function of individual mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core immunological functions of the thymus.
Data availability
Sequencing data have been deposited at ArrayExpress with accession numbers E-MTAB-8560 (ageing thymus) and E-MTAB-8737 (lineage traced thymus) or from SRA with accession number PRJNA551022 (TCR sequencing data).
-
Large-scale single cell mapping of the thymic stroma identifies a new thymic epithelial cell lineageNCBI Gene Expression Omnibus, GSE103970.
Article and author information
Author details
Irene Calvo-Asensio
Funding
Medical Research Council (MC_UU_00007/15)
- Chris P Ponting
Wellcome (105045/Z/14/Z)
- Jeanette Baran-Gale
- Michael D Morgan
- Georg A Holländer
Wellcome (109032/Z/15/Z)
- Fatima Dhalla
Swiss National Science Foundation (IZLJZ3_171050)
- Irene Calvo-Asensio
- Georg A Holländer
Swiss National Science Foundation (310030_184672)
- Irene Calvo-Asensio
- Georg A Holländer
Chan Zuckerberg Biohub
- Ashley Maynard
- Steven Chen
- Foad Green
- Rene V Sit
- Norma F Neff
- Spyros Darmanis
- Weilun Tan
- Andy P May
European Molecular Biology Laboratory (17197)
- John C Marioni
NIHR
- Adam E Handel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ellen A Robey, University of California, Berkeley, United States
Ethics
Animal experimentation: All mice were maintained under specific pathogen-free conditions and experiments were approved by the University of Oxford Clinical Medicine Ethical Review Committee and licensed under the Animals Scientific Procedures Act of the UK Home Office or Swiss cantonal and federal regulations and permissions (Permit *2321), depending where the mice were housed.
Version history
- Received: February 20, 2020
- Accepted: August 22, 2020
- Accepted Manuscript published: August 25, 2020 (version 1)
- Version of Record published: September 14, 2020 (version 2)
Copyright
© 2020, Baran-Gale et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 8,439
- views
-
- 1,109
- downloads
-
- 107
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Ageing compromises mouse thymus function and remodels epithelial cell differentiation
eLife 9:e56221.
https://doi.org/10.7554/eLife.56221
Further reading
-
- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
-
- Immunology and Inflammation
Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
