Intestinal ILC3s migrate to the kidney and promote renal fibrosis via PD-1-mediated activation
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ABSTRACT:
PROVIDER: PRJNA1050245 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27149488_1.fastq.gz | Fastqsanger.gz | |||
| SRR27149488_2.fastq.gz | Fastqsanger.gz | |||
| SRR27149489_1.fastq.gz | Fastqsanger.gz | |||
| SRR27149489_2.fastq.gz | Fastqsanger.gz | |||
| SRR27149490_1.fastq.gz | Fastqsanger.gz |
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Project description:Group 3 innate lymphoid cells (ILC3s) are enriched in mucosae, regulating inflammation and tissue repair, yet their role in renal fibrosis remains unclear. Here, we reported that renal fibrosis and dysfunction were associated with increased ILC3s in human kidney and blood. Using murine models, we showed that the rapid accumulated ILC3s in the kidney primarily originated from the intestinal mucosa. By performing scRNA-seq of ILC(3)s in kidneys and small intestines at different stage of renal fibrosis, we revealed the characteristic and migratory mechanism of these cells. Within the fibrotic kidney, ILC3s upregulated PD-1 to directly activate myofibroblasts and facilitate fibrotic niche formation by producing IL-17A. We also isolated ILCs from Pdcd1-knockout-UUO3d kidneys to gain the molecular mechanism of how PD-1 influence ILC3s' pro-fibrogenic effect. Collectively, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.
2024-05-29 | GSE249724 | GEO
Project description:IL-17D/CD93 axis was essential for ILC3s hemostasis. In order to further understand how IL-17D-CD93 axis regulate ILC3s function, we conducted RNA-seq analysis of ILC3s.
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Project description:ILC3s from the spleen (SP) and small intestine (SI) have been shown to be phenotypically and functional different. Intestinal factors are likely to regulate transcriptional profiles and thereby function of ILC3s. The goal of this study is to analyze if SI ILC3s acquire a SP-similar transcriptional profile after in vitro culture. Therefore transcriptional profiles of cultured SI ILC3s were compared to freshly isolated ILC3s of the murine SP and the SI by RNA seq technology. Cell suspension were generated from both organs and ILC3s (CD117+, Thy1.2+, KLRG1-, lin- (CD3, CD8, CD11b, CD11c, CD19, B220, Gr-1, TCRβ, TCRγδ, TER-119, NK1.1)) were sort purified. SI ILC3 were cultured for 7 days in vitro with IL-2, IL-7 and SCF. RNA was isolated and RNA sequencing was done using Ilumina Hiseq 2500 system and NuGEN Ovation RNA Seq System V2, with biological replicates. We show that intestinal ILC3 acquire a splenic-similar transcriptional profile after in vitro culture.
2020-03-17 | GSE114750 | GEO
Project description:Renal transplantation is the preferred treatment of end stage renal disease, but allograft survival is limited by development of interstitial fibrosis and tubular atrophy in response to various stimuli. Much effort has been put into identifying new protein markers of fibrosis to support the diagnosis. In present work, we performed an in-depth quantitative proteomics analysis of allograft biopsies from 31 prevalent renal transplant patients and identified correlated the quantified proteins with the volume fraction of fibrosis as determined by a morphometric method. Linear regression analysis identified four proteins that were highly associated with the degree of interstitial fibrosis, namely Coagulation Factor XIII A chain (estimate 18.7, adjusted p<0.03), Uridine Phosphorylase 1 (estimate 19.4, adjusted p<0.001), Actin-related protein 2/3 subunit 2 (estimate 34.2, adjusted p<0.05) and Cytochrome C Oxidase Assembly Factor 6 homolog (estimate -44.9, adjusted p<0.002) even after multiple testing. Proteins that were negatively associated with fibrosis (p < 0.005) were primarily related to normal metabolic processes and respiration, whereas proteins that were positively associated with fibrosis (p < 0.005) were involved in catabolic processes, cytoskeleton organization and immune response. The identified proteins may be candidates for further validation with regards to renal fibrosis. The results support the notion that cytoskeleton organization and immune responses are prevalent processes in renal allograft fibrosis.
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Project description:Group 3 innate lymphoid cells (ILC3s) are critical regulators of intestinal homeostasis, yet their role in cancer remains elusive. Here, we identify that the tumor microenvironment of humans and mice with colorectal cancer (CRC) contains altered ILC3 responses that resemble those found during intestinal inflammation and are characterized by reduced frequencies, altered subset distribution, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that ILC3-specific major histocompatibility complex class II (MHCII) was required to limit the progression of CRC. Interestingly, ILC3-specific MHCII also prevented resistance to anti-PD-1 immunotherapy by regulating intestinal inflammation and microbiota composition. Finally, humans with intestinal inflammation and dysregulated ILC3s also harbor specific microbiota that are sufficient to promote immunotherapy resistance in mice. Collectively, these data define a protective role for antigen-presenting ILC3s in cancer, and indicate that inherent disruption of this pathway drives CRC progression and immunotherapy resistance.
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Project description:Pre-treatment tumor expression of PD-L1 has been shown to correlate with favorable clinical outcomes following PD-1 blocking therapies. However, the majority of patients with PD-L1+ tumors do not respond to treatment. With the goal of obtaining insights into the mechanisms underlying the response to anti-PD-1 targeted therapies in patients with renal cell carcinoma (RCC) with positive tumor expression of PD-L1, microarray expression data was obtained for pre-treatment tumors from patients with RCC who did or did not have a positive response to anti-PD-1 (nivolumab) therapy. Insight into these mechanisms may lead to improved rationally designed therapies, and biomarkers for selecting patients who are more likely to benefit from these treatments. Gene expression profiling was performed on total RNA extracted from 11 formalin-fixed paraffin-embedded (FFPE) RCC specimens, 4 of which were from patients who had a positive response (objective tumor regression) to the anti-PD-1 (nivolumab) immunotherapy, and 7 of which were from patients who did not have a response. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Maria Libera Ascierto, Tracee L. McMiller, Alan E. Berger, Ludmila Danilova, Robert A. Anders, George J. Netto, Haiying Xu, Theresa S. Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G. Drake, Drew M. Pardoll, Janis M. Taube, and Suzanne L. Topalian, The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Antiâ??PD-1 Response in Patients with Renal Cell Carcinoma, published online in Cancer Immunology Research on 4 August 2016, doi: 10.1158/2326-6066.CIR-16-0072 http://cancerimmunolres.aacrjournals.org/content/early/2016/07/28/2326-6066.CIR-16-0072.full.pdf+html
2016-08-04 | E-GEOD-67501 | biostudies-arrayexpress
Project description:Innate lymphoid cells (ILCs) are tissue-resident lymphocytes subdivided into ILC1s, ILC2s and ILC3s based on core regulatory programs and signature cytokines secreted. ILCs exhibit functional plasticity: for instance, human IL-22-producing ILC3s convert into IFN-γ-producing ILC1-like in vitro. Whether this conversion occurs in vivo is unclear. Using flow cytometry, mass cytometry and scRNAseq, here we found that ILC3s and ILC1s occupy opposite ends of a spectrum including discrete subsets in human tonsils. RNA velocity suggested strong directionality toward ILC1s for one ILC3-ILC1 intermediate cluster. Clonal analysis revealed graded ability of ILC3-ILC1 subsets to convert into ILC1-like cells. When examined in humanized mice, ILC3 acquisition of ILC1 features showed tissue-dependency. In chromatin studies, Aiolos emerged as a nuclear factor that cooperates with Tbet to repress evolutionarily conserved regulatory elements active in ILC3s. The human intestine also exhibited an ILC3–ILC1 transitional population. We conclude that conversion of ILC3s to ILC1-like occurs in vivo in human tissues, and that tissue factors and Aiolos are crucial for this process.
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Project description:Human ILCs are classically categorized into five subsets; cytotoxic CD127-CD94+ NK cells and non-cytotoxic CD127+CD94-, ILC1s, ILC2s, ILC3s and LTi cells. Here, we identify a novel subset within the CD127+ ILC population, characterized by the expression of the cytotoxic marker CD94. These CD94+ ILCs strongly resemble conventional ILC3s in terms of phenotype, transcriptome and cytokine production, but are highly cytotoxic. IL-15 was unable to induce differentiation of CD94+ ILCs towards mature NK cells. Instead, CD94+ ILCs retained RORγt, CD127 and CD200R expression and produced IL-22 in response to IL-15. Culturing non-cytotoxic CD127+ ILC1s or ILC3s with IL-12 induced upregulation of CD94 and cytotoxic activity, effects that were not observed with IL-15 stimulation. Thus, human helper ILCs can acquire a cytotoxic program without differentiating into NK cells.
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