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Eosinophil-derived COX-2 protects against experimental colitis through the PGE2–IL-22 axis

ABSTRACT: Inflammatory bowel disease (IBD) is driven by a breakdown in immune regulation and epithelial barrier function, yet the contribution of eosinophils to this process has remained poorly defined and controversial. While eosinophils infiltrate the intestinal mucosa during both flares and remission, their role in shaping disease outcomes is unclear. Our RNA-seq analyses of colonic eosinophils isolated from dextran sulfate sodium (DSS)-treated mice revealed a significant upregulation of cyclooxygenase (COX)-2 (gene name, Ptgs2). Eosinophil-specific deletion of COX-2 (Ptgs2fl/fleoCre+/−) reduced IL-22 production and exacerbated DSS- and trinitrobenzene sulfonic acid (TNBS)-induced colitis, characterized by greater weight loss, higher disease activity, colon shortening, and epithelial injury. Administration of recombinant IL-22 reversed these phenotypes. Mechanistically, eosinophil-derived COX-2 enhanced IL-22 production by type 3 Innate lymphoid cells (ILC3s) through prostaglandin E2 (PGE2) signaling. Consistently, Ptgs2fl/fleoCre+/− mice exhibited reduced colonic PGE2 levels, while PGE2 analog treatment restored IL-22 production and mucosal protection. Our findings identify eosinophil-derived COX-2 and PGE2 as a critical regulator of IL-22 production during colitis, uncovering a eosinophil–ILC3 cross talk that safeguards the intestinal barrier and represents a promising therapeutic target in IBD.

ORGANISM(S): Mus musculus

PROVIDER: GSE328526 | GEO | 2026/04/23

REPOSITORIES: GEO

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Eosinophil-derived COX-2 protects against experimental colitis through the PGE2–IL-22 axis

Project description:Eosinophil-derived COX-2 protects against experimental colitis through the PGE2–IL-22 axis

| PRJNA1455599 | ENA

IL-33 markedly induces murine eosinophil gene transcription via autocrine IL-4-dependent and -independent mechanisms

Project description:Eosinophils are major effector cells in type 2 inflammatory responses and become activated in response to IL-4 and IL-33, yet the molecular mechanism remains unclear. We examined the direct effect of these cytokines on eosinophils and demonstrated that murine eosinophils respond to IL-4 and IL-33 by phosphorylation of STAT-6 and NFkB, respectively. RNA sequencing analysis of murine eosinophils indicated that IL-33 regulates 519 genes, whereas IL-4 regulates only 28 genes, including 19 IL-33-regulated genes. Interestingly, IL-33 induced eosinophil activation via two distinct mechanisms, IL-4 independent and IL-4 secretion/auto-stimulation dependent. Anti-IL-4 or anti-IL-4Ra antibody-treated eosinophils, as well as Il4- or Stat6-deficient eosinophils, had attenuated protein secretion of a subset of IL-33-induced genes, including Retnla and Ccl17. However, the induction of most IL-33-regulated transcripts (e.g. Il6 and Il13) was IL-4 independent and blocked by NFkB inhibition. Indeed, IL-33 induced the rapid release of pre-formed IL-4 protein from eosinophils by an NFkB-dependent mechanism. Thus, we have identified a novel activation pathway in murine eosinophils that is induced by IL-33 and differentially dependent upon IL-4. These data suggest that IL-4 plays a critical role in auto-amplification of IL-33-induced eosinophil activation and could be a potential target for therapeutic approaches in IL-33-related eosinophil-associated diseases. Low density bone marrow derived murine eosinophils were generated in culture over the period of 14 days. Eosinophils were activated by either IL-33 or IL-4 at 10 ng/ml for 1hr and 4hr. RNA was collected and subjected to next generation sequencing.

2013-08-01 | E-GEOD-43660 | biostudies-arrayexpress

Transcriptional analysis of TREM-1+ and TREM-1- airway eosinophils during allergic inflammation

Project description:Triggering Receptor Expressed on Myeloid cells 1 (TREM-1) an innate receptor that canonically amplifies inflammatory signaling in neutrophils and monocytes, plays a central role in regulating lung inflammation. Utilizing a murine model of asthma, flow cytometry revealed TREM-1+ eosinophils in the lung tissue and airway during allergic airway inflammation. TREM-1 expression was restricted to recruited, inflammatory eosinophils. Expression was induced on bone marrow derived eosinophils by incubation with IL-33, LPS, or GM-CSF. Compared to TREM-1- airway eosinophils, TREM-1+ eosinophils were enriched for pro-inflammatory gene sets including migration, respiratory burst, and cytokine production. Unexpectedly, eosinophil-specific ablation of TREM-1 increased airway IL-5 and lung tissue eosinophil accumulation. Further investigation of transcriptional data revealed apoptosis related gene sets were enriched in TREM-1+ eosinophils. Annexin V staining demonstrated higher rates of apoptosis among TREM-1+ eosinophils compared to TREM-1- eosinophils in the inflammatory airway. In vitro, Trem1/3-/- eosinophils were protected from apoptosis. Finally, inhibition of reactive oxygen species production with diphenyleneiodonium protected WT bone marrow derived eosinophils from apoptosis more than Trem1/3-/- eosinophils, suggesting that superoxide accounted for more apoptosis in WT cells. These data demonstrate protein level expression of TREM-1 by eosinophils for the first time, define a population of TREM-1+ inflammatory eosinophils, and reveal that eosinophil TREM-1 restricts key features of type 2 lung inflammation.

2023-12-15 | GSE246389 | GEO

Global transcriptomic analysis of colons of wild type and NLRX1-/- mice with IBD

Project description:NLRX1 is a mitochondrial-associated NOD-like receptor that modulates antiviral immunity, cellular stress, autophagy, and reactive oxygen species (ROS) production. The role of NLRX1 in inflammatory bowel disease (IBD) remains largely unknown. This study aimed to characterize NLRX1-mediated mechanisms of protection from IBD. We investigated the ability of NLRX1 to modulate global colonic gene expression, gut pathology, inflammation and immunity by using loss-of-function approaches in dextran sodiu sulfate (DSS) and CD4+CD45RBhigh transfer colitis models. Colons, spleens, and mesenteric lymph nodes (MLN) were excised for characterizing immune cell subsets, histological analyses, cytokine, RNA sequencing analyses, and autophagy expression, NF-κB activity, and ROS production. The loss of NLRX1 increased severity of disease and colonic histopathology in both models of IBD. Colons of NLRX1-/- mice had significantly increased epithelial ulceration and leukocyte infiltration mostly in the form of neutrophils, lymphocytes, and macrophages in the DSS model, while recipients of NLRX1-/- CD4+ T cells had increased leukocytic infiltration, proliferation, fibrosis, and crypt abscessation in both colon and ileum. The loss of NLRX1 increased numbers of effector T helper (Th1), Th17, and regulatory T cells (Treg) cells in the colonic mucosa and spleen, increased colonic NF-κB activity, upregulation of IL-17, IFNγ and TNF-α production, and increased ROS production. Global transcriptomic analyses demonstrates that NLRX1 regulates immunity and lipid metabolism pathways. NLRX1 ameliorates intestinal pathology during IBD by acting as an internal thermostat that modulates the balance of effector versus regulatory CD4+ T cell responses, and suppressing colonic NF-κB activity, inflammatory cytokine expression, lipid metabolism gene expression, ROS production and autophagy.

2018-03-07 | GSE68419 | 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

Transcriptional profiling of eosinophil subsets in Interleukin-5 transgenic mice

Project description:Eosinophils are important in fighting parasitic infections and are implicated in the pathogenesis of asthma and allergy. Interleukin-5 (IL-5) is a critical regulator of eosinophil development, controlling proliferation, differentiation and maturation of the lineage. Mice that constitutively express IL-5 have more than 10 fold more eosinophils in the haematopoietic organs than their wild type counterparts. We have identified that much of this expansion is in a population of Siglec-F high eosinophils, which are rare in wild type mice. In this study we assessed transcription in myeloid progenitors, eosinophil precursors and Siglec-F medium and Siglec-F high eosinophils from IL-5 transgenic mice and in doing so have created a useful resource for eosinophil biologists. We have then utilised these populations to construct an eosinophil trajectory based on gene expression and to identify gene sets that are associated with eosinophil lineage progression. Cell cycle genes were significantly associated with the trajectory, and we experimentally demonstrate an increasing trend towards quiescence along the trajectory. Additionally we found gene expression changes associated with constitutive IL-5 signalling in eosinophil progenitors, many of which were not observed in eosinophils.

2018-03-20 | GSE112010 | GEO

Transcription factor ELF-1 protects against colitis by maintaining intestinal epithelium homeostasis

Project description:Inflammatory bowel disease (IBD) is a chronic, relapsing, and remitting disease characterized by chronic inflammation in the gastrointestinal tract. The exact etiology and pathogenesis of IBD remain elusive. Although ELF-1 has been known to be highly expressed in epithelial cells for past twenty years, little is known about its function in epithelial cells and epithelial-related IBD. Here, we demonstrated that ELF-1 deficiency in mouse lead to exacerbated DSS-induced colitis, marked by inflammation dominated by neutrophil infiltration and activation of IL-17 signaling pathways in various immune cells, including Th17, ILC3, γδT and NKT cells. Bone marrow transfer experiments confirmed ELF-1 deficiency in non-hematopoietic cells intrinsically worsened DSS-induced colitis. On one hand, ELF-1 deficiency enhanced the production of pro-inflammatory chemokines in colonic epithelial cells, leading to extensive infiltration of neutrophils and other immune cells into the colonic mucosal tissue. On the other hand, ELF-1 directly regulated the expression of the Rack1 gene in colonic epithelial tissue, which has been proved to play critical roles in maintaining intestinal homeostasis. Altogether, ELF-1 plays a protective role in colitis by maintaining intestinal epithelium homeostasis.

2025-02-12 | GSE289183 | GEO

Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells

Project description:We compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1β induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE2 production and increased PGF2α and thromboxane B2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways.

2019-05-20 | PXD013490 | Pride

Enrichment of type I interferon signaling in colonic group 2 innate lymphoid cells in experimental colitis

Project description:Group 2 innate lymphoid cells (ILC2) are enriched in colonic tissues, but their precise role under intestinal inflammation, including inflammatory bowel disease (IBD) other than helminth infection, is poorly understood. Here, we analysed global gene expression of colonic ILC2 in healthy and colitis mice and found that type I interferon (T1IFN)-stimulated genes (ISGs) are enriched in ILC2 under DSS-induced colitis. Enhancement of T1IFN signaling in ILC2 under DSS-induced colitis were correlated to downregulation in cytokine production of ILC2, such as IL-5. Blocking T1IFN signaling during colitis resulted in exaggeration of colitis both in wild-type and Rag2-deficient mice. Collectively, these findings show the potential roles of T1IFN in ILC2 contributing to the development of colitis.

2022-09-21 | GSE212939 | GEO

USP2 promotes experimental colitis and bacterial infections by inhibiting the proliferation of myeloid cells and remodeling the extracellular matrix network

Project description:Inflammatory bowel disease (IBD) is closely associated with dysregulation of genetic factors and microbial environment. Here, we report a susceptible role of ubiquitin-specific protease 2 (USP2) in experimental colitis and bacterial infections. USP2 is upregulated in the inflamed mucosa of IBD patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout or pharmacologic inhibition of USP2 promotes the proliferation of myeloid cells to activate IL-22 and IFNg production of T cells. In addition, knockout of USP2 in myeloid cells inhibits the production of pro-inflammatory cytokines to relieve the dysregulation of extracellular matrix (ECM) network and promote the gut epithelial integrity after DSS treatment. Consistently, Lyz2-Cre;Usp2fl/fl mice exhibit hyper-resistance to DSS-induced colitis and Citrobacter rodentium infections compared to Usp2fl/fl mice. These findings highlight an indispensable role of USP2 in myeloid cells to modulate T cell activation and epithelial ECM network and repair, indicating USP2 as a potential target for therapeutic intervention of IBD and bacterial infections in the gastrointestinal system.

2022-07-18 | GSE208325 | GEO

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