Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Fibroblast-ILC3 crosstalk restrains inflammation in the gut

ABSTRACT: Fibroblasts exhibit remarkable phenotypic and functional heterogeneity in chronic inflammatory diseases, but how these changes impact immune outcomes remain at early stages of investigation. Here we identify a unique fibroblast population that robustly expresses insulin-like growth factor 1 (IGF1) in the healthy intestine that are reduced in inflammatory bowel disease (IBD) patients and necessary to protect from experimental models of gut inflammation. In silico analyses reveal unexpected cross-talk between IGF1+ fibroblasts and group 3 innate lymphoid cells (ILC3s), which dominantly express the IGF-1 receptor (IGF1R) in the gut to protect from inflammation. Mechanistically, IGF1 limits ILC3 production of CXCL10 in inflammatory contexts to prevent recruitment of plasmacytoid dendritic cells (pDC) and restrain gut inflammation. Finally, IGF1 signaling reduces CXCL10 production in human ILC3s, but this pathway is altered in the inflamed intestine of IBD patients and inversely correlates with a higher frequency of pDC. Our results define an unexpected mechanism by which anti-inflammatory fibroblasts safeguard the gut by IGF1-dependent crosstalk with an innate lymphocyte-pDC axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE328564 | GEO | 2026/06/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

IRE1α-XBP1 sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease

Project description:Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. Endoplasmic reticulum (ER) stress is linked to inflammatory bowel disease (IBD). Herein, we used cell culture, novel mouse models, and human specimens to examine if ER stress in ILC3s impacts IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24h-rhythmic expression pattern of the master ER stress response regulator, IRE1α-XBP1. Proinflammatory cytokine IL-23 selectively stimulated IRE1α-XBP1 in mouse ILC3s through mitochondrial reactive oxygen species (mtROS). IRE1α-XBP1 was activated in ILC3s of mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in Crohn’s disease patients before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with response to treatment. We demonstrate that a non-canonical mtROS-IRE1α-XBP1 pathway augments cytokine production by ILC3s and identify XBP1+ ILC3s as a potential biomarker for predicting response to anti-IL-23 therapies in IBD. Group 3 innate lymphoid cells (ILC3s) have recently emerged as important regulators and potential drug targets for IBD. However, the response of ILC3s to environmental stimuli during intestinal inflammation remains elusive. IRE1a-XBP1 serves as the regulatory hub of the unfolded protein response (UPR) that plays a vital role in intestinal inflammation.

2024-05-31 | GSE261091 | GEO

DAB2IP modulates intestinal inflammation by enhancing ILC3 function in the gut

Project description:Group 3 innate lymphoid cells (ILC3s) protect the intestinal barrier by producing IL-22 and IL-17A, yet the molecular mechanisms that sustain their cytokine output during inflammation remain poorly defined. Here, we identify the cytosolic scaffold DAB2IP as a critical ILC3-intrinsic regulator of effector function. In human IBD, DAB2IP expression is reduced in inflamed tissues, correlating with impaired epithelial repair and decreased IL-22. In mice, DAB2IP expression in ILC3s declines during intestinal inflammation, and silencing DAB2IP markedly diminishes IL-22 and IL-17A production. Adoptive transfer of Dap2ip-deficient ILC3s exacerbates DSS-induced colitis and increases susceptibility to Citrobacter rodentium. Mechanistically, DAB2IP promotes NF-κB activation, sustaining transcription of Il22 and Il17a. These results reveal a context-dependent role for DAB2IP as a positive regulator of NF-κB in ILC3s, highlighting its previously unknown function in mucosal immunity and epithelial repair, and suggesting that restoring DAB2IP signaling could enhance barrier protection during intestinal inflammation.

2026-02-25 | GSE310552 | GEO

Chromatin accessibility landscapes of WT (Rag1-/-) and BATF KO (Rag1-/-Batf-/-) ILC3s sorted from small intestine [ATAC-seq]

Project description:Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s, and ILC3s-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3s homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by removal of adaptive immunity or antibiotic treatment. Mechanistically, BATF directly regulates ILC3s identity by globally shapes chromatin landscape of ILC3s. BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways. Collectively, our findings reveal BATF is a promising candidate to maintain ILC3s stability and coordinate ILC3s–mediated control of intestinal homeostasis.

2022-08-31 | GSE168078 | GEO

Bulk RNA sequencing of WT (Batf fl/fl) and Batf-/- (Batf fl/fl PLZFcre+) ILC3s sorted from small intestine [bulk RNA-seq]

2022-08-31 | GSE168076 | GEO

Chromatin accessibility landscapes of intestinal WT Nkp46-CC6- ILC3 (Double Negative, DN ILC3) and BATF-deficient cKO DN ILC3s sorted from intestine

2022-09-08 | GSE212590 | GEO

Characterization of small intestine innate lymphoid cells of WT (Batf fl/fl) and cKO (Batf fl/fl Plzf cre+) mice using single cell RNA sequence [scRNA-seq]

2022-08-31 | GSE168077 | GEO

ChIP-seq analysis of BATF in ILC3s sorted from small intestine of Rag1-/- mice [CUT&TAG ChIPseq]

2022-08-31 | GSE168079 | GEO

Nucleophosmin 1 Promotes Mucosal Immunity by Supporting Mitochondrial Oxidative Phosphorylation and ILC3 Activity

Project description:NPM1 is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Concurrent inflammatory bowel diseases (IBD) and MDS have been reported frequently, indicating a close relationship between IBD and MDS. Here, we examined the role of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 was reduced in IBD patients. Npm1+/- mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of IL-22-producing group 3 innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote TFAM transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced severity of DSS-induced colitis. Thus, our findings suggest the protective function of NPM1 in ILC3s against IBD by regulating mitochondrial metabolism through p65-TFAM axis.

2024-07-09 | GSE271455 | GEO

The TNFSF12/TWEAK modulates colonic inflammatory fibroblast differentiation and promotes fibroblast-monocyte interactions

Project description:Fibroblasts acquire a pro-inflammatory phenotype in inflammatory bowel disease (IBD), but the factors driving this process and how fibroblasts contribute to the immune response is incompletely understood. The TNF superfamily factor 12 (TWEAK) has gained interest as a mediator of chronic inflammation. Here, we explore its role as a driver of inflammatory responses in fibroblasts and its contribution to fibroblast-monocyte interaction using human primary colonic fibroblasts, THP1 and peripheral blood mononuclear cells (PBMC). TWEAK induced the expression of cytokines, chemokines and immune receptors in fibroblasts. The TWEAK up-regulated transcriptome shared 29% homology with the previously published transcriptional profile of inflammatory fibroblasts from ulcerative colitis. TWEAK elevated surface expression of activated fibroblasts markers and adhesion molecules (PDPN, ICAM-1 and VCAM-1) and secretion of IL-6, CCL2 and CXCL10. In co-culture, fibroblasts induced monocyte adhesion and promoted a CD14high/ICAM-1 high phenotype in THP1 cells, both of which were enhanced when fibroblasts were pre-stimulated with TWEAK. Medium from TWEAK-treated fibroblast-THP1 co-cultures had elevated levels of CXCL1 and IL-8. PBMCs in co-culture with TWEAK-treated fibroblasts had altered surface expression of CCR2 and CD16, and increased CXCL1 and CXCL10. Our results indicate that TWEAK promotes and inflammatory fibroblast-monocyte crosstalk that may be amenable for therapeutic intervention.

2024-04-23 | GSE237845 | GEO

RNA sequencing of sort-purified ILC3s from IBD patients

Project description:Group 3 innate lymphoid cells (ILC3s) are abundant in the developing or healthy intestine to critically support tissue homeostasis in response to microbial cues and other environmental signals. However, during gastrointestinal disease including infections, colorectal cancer, or inflammatory bowel disease (IBD), intestinal ILC3 numbers are dramatically reduced and the remaining ILC3s become dysfunctional which fuels disease and barrier breakdown. To define the underlying transcriptomic changes, we employed RNA sequencing of ILC3s from IBD patients. This may help to gain a deeper understanding of the mechanisms driving these alterations and ultimately lead to novel preventive, diagnostic, or therapeutic opportunities in IBD.

2024-04-23 | GSE247742 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data