Androgens protect murine ILC2 cells from functional suppression during influenza virus infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA788976 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17232127.fastq.gz | Fastqsanger.gz | |||
| SRR17232128.fastq.gz | Fastqsanger.gz |
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Project description:Lung-resident group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines and facilitate tissue repair in response to alarmins such as IL-33 released during respiratory virus infection, but they also may be functionally suppressed by type 1 cytokines. Compared to females, males harbor significantly fewer lung ILC2s, which express notably high levels of androgen receptor (AR) compared to other lymphocytes. Here we tested the hypothesis that females and males show differential ILC2 responses upon influenza virus (IAV) infection of mice. Over the course of sublethal infection, lungs of female mice contained greater numbers of ILC2s and ILC1s compared to males. However, the female ILC2s were preferentially suppressed at the peak of infection, with a dampened type 2 program manifest as attenuated proliferation, decreased propensity to produce IL-5 and amphiregulin, and reduced expression of GATA3 and IL-33R. Naïve female ILC2s showed higher expression of IFNGR and higher phospho-STAT1 levels following stimulation by IFN, and lymphocyte-restricted STAT1 deficiency reversed suppression of female ILC2s during infection. ILC2s in naive male mice with lymphocyte-restricted AR deficiency displayed levels of IFNGR comparable to female mice, suggesting AR activity underlies sex differences in intrinsic IFNGR expression. Early life orchiectomy or lymphocyte-restricted loss of AR revealed that endogenous androgens decreased ILC2 numbers but protected males from suppression of ILC2s in IAV infection. In sum, intrinsic AR activity preserves canonical ILC2 function in males during IAV infection, which may contribute to the sex differences in morbidity secondary to IAV observed in mice and humans.
2024-12-13 | GSE190941 | GEO
Project description:Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens – including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals, but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 were found to be uniquely pre-primed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine producing capacity of ILC2. Moreover, amino acid determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.
2022-12-22 | PXD038792 | Pride
Project description:Group 2 innate lymphoid cells (ILC2s) exert critical roles in anti-helminth immunity and the pathogenesis of allergic diseases by rapidly secreting vast amounts of type 2 signature cytokines. Type 1 interferons (IFN-I) are critical negative regulators of ILC2 effector functions and associated innate and adaptive type 2 immunopathologies. Exposure to IFN-I inhibits ILC2 proliferation as well as type 2 cytokine production, however, the mechanistic underpinnings of IFN-I-mediated ILC2 regulation remain largely elusive. Using RNA-sequencing analysis, we demonstrate that IFN-I treatment inhibits the production of the chemokine CCL1 by ILC2s. Moreover, expression of CCR8, the cognate chemokine receptor for CCL1, is downregulated upon IFN-I-stimulation ex vivo as well as in vivo upon sublethal influenza A virus infection (IAV) or upon IFN-I administration following pulmonary IL-33 challenge. In addition, expression of CCL8, the chemotactic ligand of CCR8, was suppressed in an IFN-I dependent manner in the lungs of IAV-infected mice. IFN-b potently restrained pulmonary CCL1/CCL8 expression as well as CCR8 expression by ILC2 and CD4+ T cells in a model of IL-33-driven allergic airway inflammation. Thus, this study sheds new light on the underlying mechanisms of ILC2 regulation by identifying the CCR8-CCL1/CCL8 axis as a target for IFN-I-driven ILC2 inhibition.
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Project description:The spatial organization of chromatin is known to be highly dynamic in response to environmental stress. However, it remains unknown how chromatin dynamics contributes to or modulate the disease pathogenesis. Here we show that upon influenza virus infection, H4K20me3 methyltransferase Suv4-20h2 binds the viral protein NP, which results in the inactivation of the Suv4-20h2 and the dissociation of cohesin from Suv4-20h2. Inactivation of Suv4-20h2 by virus infection or genetic deletion, leads to active loop formation at HoxC8-HoxC6 through the loading of cohesin to this region. HoxC8 and HoxC6 in turn enhance viral replication by inhibiting the Wnt--catenin mediated interferon response. Importantly, loss of Suv4-20h2 augments the influenza pathology in vivo. Thus, Suv4-20h2 acts as a safeguard against influenza virus infection though the suppression of a cohesin-mediated loop formation.
2021-05-13 | PXD025676 | Pride
Project description:Viral infection is commonly associated with virus-driven hijacking of host proteins. We describe a novel mechanism by which influenza virus impacts host cells through the interaction of influenza NS1 protein with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 target the transcription elongation PAF1 complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C results in suppression of hPAF1C-mediated transcriptional elongation. In the following data sets, we show that NS1 colocalizes with hPAF1 on the chromatin of infected cells and that siRNA-mediated reduction of hPAF1 expression results in reduced recruitment of NS1 to the chromatin.
2013-07-01 | GSE35774 | GEO
Project description:Viral infection is commonly associated with virus-driven hijacking of host proteins. We describe a novel mechanism by which influenza virus impacts host cells through the interaction of influenza NS1 protein with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 target the transcription elongation PAF1 complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C results in suppression of hPAF1C-mediated transcriptional elongation. In the following data sets, we show that NS1 colocalizes with hPAF1 on the chromatin of infected cells and that siRNA-mediated reduction of hPAF1 expression results in reduced recruitment of NS1 to the chromatin. Examination of different histone modifications in infected cells and RNA-Seq and GRO-Seq transcript measurements.
2013-07-01 | E-GEOD-35774 | biostudies-arrayexpress
Project description:ILC2 cells are a newly described cell type whose biology and contribution to disease are poorly understood. ILC2 cells are activated by allergens, viral infection, and/or epithelial damage via IL-33 and IL-25. ILC2 cells require IL-2, IL-7, IL-25 and IL-33 for their survival and expansion. In mice, ILC2s produce multiple mediators primarily associated with type 2 inflammation (IL-13, IL-5, IL-4, IL-6, IL-9, IL-10, GM-CSF, amphiregulin). ILC2 cells may contribute to the pathology of asthma through multiple mediators that include IL-13-independent pathways. Our goal is to compare transcriptional profiles of IL-33- or IL-25-activated ILC2 cells from blood to characterize these cells and to identify marker(s) that can be utilized to detect them in human tissue. ILC2 cells (Lineage negative, CRTH2+, CD161+, CD127+) were purified from human blood of 5 different donors by flow cytometry. The ILC2 yield ranged from 20,000 to 165,000 cells per donor (0.001-0.008% WBC). Purified ILC2s were expanded in vitro in the presence of IL-2, IL-7, IL-33 and IL-25 (each at 50 ng/ml) for 7-10 days. Expanded cells maintained the ILC2 phenotype (Lineage negative, CRTH2+, CD161+, CD127+). The cells were rested for 2 days in the presence of 1 ng/ml IL-2 and IL-7 and then treated in the presence of 1 ng/ml IL-2 and IL-7 with either media control, IL-25 (50 ng/ml), IL-33 (50 ng/ml), and/or TSLP (50 ng/ml) in combination, for 6 or 24 hours. Whole RNA was isolated via the RNeasy kit (Qiagen). Stratagene Universal Human Reference RNA was used as the reference.
2013-12-31 | E-GEOD-45458 | biostudies-arrayexpress
Project description:Introduction: Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer (PCa). The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene-expression. Design: Androgen levels and androgen-regulated gene-expression (by microarray-profiling, qRT-PCR and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the GnRH-antagonist, Acyline, vs. placebo in healthy men. To assess the effects of long-term ADT, gene-expression measurements were evaluated at baseline and after 3, 6 and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized PCa. Results: Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and PSA, were not suppressed after short-term castration, nor after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in PCa samples at each time-point of ADT. Conclusions: Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene-expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing PCa cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment. Keywords: prostate, androgen, Acyline, microarray, immunohistochemistry
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Project description:The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2 ILC2 cells isolated from ETS1-deleted or litter mate control mice were cultured on OP9-DL1 with IL-7 and IL-33. Subsequently, RNA from ICOS+ cells was extracted, labelled and hybridized to Affymetrix microarrays. The goal of this study is to investigate ETS1-dependent genes in developing ILC2 cells.
2016-04-01 | E-GEOD-79742 | biostudies-arrayexpress