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Deconvolution of myeloid cell cytokine specific transcriptional profiles during tuberculosis and cancer identifies neutrophil activation as a prognostic feature [cultured cells]

ABSTRACT: The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could guide therapy or predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils to stimulation by type 1 cytokines (IFN-g, IFN-b and IFN-l) type 2 cytokines (IL-4 and IL-13) and the immunoregulatory cytokine IL-10. This generated a myeloid cell cytokine specific response matrix to infer representation of myeloid cells and the cytokine environment they may encounter during infection and in tumors. Neutrophils were surprisingly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-b stimulation, whereas other IFN signature genes were upregulated by both IFN-g and IFN-b. When used to deconvolute blood profiles from tuberculosis patients, the IFN-b specific neutrophil signature was surprisingly reduced in TB patients with active disease whereas the shared response to IFN-g and IFN-b in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-g or IFN-b emerged as opposing predictors of survival in samples from patients with glioma. This approach may help delineate biological roles for myeloid cells in different cytokine environments during disease processes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131990 | GEO | 2019/10/01

REPOSITORIES: GEO

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Deconvolution of myeloid cell cytokine specific transcriptional profiles during tuberculosis and cancer identifies neutrophil activation as a prognostic feature [whole blood]

Project description:The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could guide therapy or predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils to stimulation by type 1 cytokines (IFN-g, IFN-b and IFN-l) type 2 cytokines (IL-4 and IL-13) and the immunoregulatory cytokine IL-10. This generated a myeloid cell cytokine specific response matrix to infer representation of myeloid cells and the cytokine environment they may encounter during infection and in tumors. Neutrophils were surprisingly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-b stimulation, whereas other IFN signature genes were upregulated by both IFN-g and IFN-b. When used to deconvolute blood profiles from tuberculosis patients, the IFN-b specific neutrophil signature was surprisingly reduced in TB patients with active disease whereas the shared response to IFN-g and IFN-b in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-g or IFN-b emerged as opposing predictors of survival in samples from patients with glioma. This approach may help delineate biological roles for myeloid cells in different cytokine environments during disease processes.

2020-02-21 | GSE145647 | GEO

IL-1B signaling in dendritic cells induces antiviral interferon responses

Project description:Activation of interferon-stimulated gene (ISG) responses is critical for control of viral infection. We recently identified that stimulation of the NLRP3 inflammasome and mobilization of the inflammatory cytokine IL-1β act as critical host restrictive pathways against West Nile virus (WNV) in a mechanism dependent on the regulation of ISGs. In order to define the mechanism by which IL-1β regulates these antiviral immune programs, we utilized global transcriptome analysis in myeloid cells, known targets of WNV replication to define gene signatures required for IL-1β driven antiviral responses. Surprisingly, we found IL-1β dependent activation of interferon-beta (IFN-β) and ISGs at late times following IL-1β treatment. Expression of these antiviral innate immune genes was found to be dependent on activation of IRF3 and appears to reflect a general shift in IL-1β signaling from an inflammatory response early following treatment to an anti-inflammatory type-I IFN mediated response at later times post-treatment. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection. Strategies to co-opt these cytokine activated antiviral signatures can act as novel targeted therapeutic strategies tailored specifically to individual pathogens.

2018-01-12 | GSE109069 | GEO

eQTL Interactions in Lupus Patients

Project description:<p>The purpose of this study is to discover in vivo cytokine expression quantitative trait locus (eQTL) interactions from a cohort of patients with systemic lupus erythematosus. 157 lupus patients were enrolled in a clinical trial to test the efficacy and safety of an anti-IL-6 monoclonal antibody. At three time points, we measured interferon (IFN) status, anti-IL-6 drug exposure and genome-wide gen expression. We identified 4,818 cis-eQTLs and then observed a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 exposure.</p>

| phs001702 | dbGaP

Type 2 innate signals regulate functionality of fibro/adipogenic progenitors to facilitate muscle regeneration

Project description:In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis, while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues. Fibroadipocyte progenitors were isolated from wild-type and IL-4Ra knockout (IL-4Ra -/-) mice and were treated with vehicle or IL4 stimulation in culture prior to microarray analysis. 4 biological replicates of each condition were performed.

2013-04-11 | E-GEOD-44933 | biostudies-arrayexpress

Neutrophil activation by IL-4, IL-13 and IFN-g

Project description:Interleukin (IL)-4 and IL-13 are related cytokines with well-known roles in type 2 immune response. However, their effects on neutrophils are less defined and existing research has provided somewhat contradictory results We measured IL-4-, IL-13- and IFN-g-stimulated gene expression in highly purified human neutrophils.

2023-03-28 | GSE218535 | GEO

Gene expression profiling of sarcoma T cells deriving from Csf3r WT and KO mice

Project description:Recently, tumor-associated neutrophils (TANs) are considered as an important component of the tumor microenvironment. Here, we show that a specific genetic deficiency of neutrophils induced accelerated mesenchymal carcinogenesis associated with a deficient production of IFN-γ in the tumor microenvironment. Unexpectedly, increased susceptibility to cancer of neutropenic mice was associated with impaired type 1 polarization of unconventional T cell (UTC) subsets, namely mucosal-associated invariant T (MAIT) cells and double CD4 and CD8 negative TCRβ+ T (DNT) cells, resulting in reduced expression of T-bet and IFN-γ and increased expression of Rorγt and IL-17A. Here, we uncovered a new mechanism by which neutrophils induced an IL-12-dependent type 1 polarization of MAIT and DNT cells characterized by the upregulation of T-bet expression. Therefore, a systemic reconstitution of Csf3r-/- mice with functional naïve neutrophils was sufficient to restore UTCs activation state and to slow down sarcoma growth. Finally, in patients with undifferentiated pleomorphic sarcoma, TAN infiltration signature was associated with better overall survival and increased expression of IFN-γ and type 1 inflammatory response signature.

2019-06-24 | GSE109031 | GEO

Interleukin-10 causes interferon-γ-dependent emergency myelopoiesis

Project description:In emergency myelopoiesis (EM), expansion of the myeloid progenitor compartment and increased myeloid cell production is observed, often mediated by the pro-inflammatory cytokine IFN-γ. IL-10 inhibits IFN-γ secretion, largely by its effects on macrophages and dendritic cells, but, paradoxically, its therapeutic administration to humans causes hematologic changes similar to those observed in EM. In this work we used different in vivo systems, including a humanized immune system mouse model, to show that IL-10 triggers EM, with a significant expansion of the myeloid progenitor compartment and production of myeloid cells. Hematopoietic progenitors display a prominent IFN-γ transcriptional signature, and we show that IFN-γ mediates IL-10-driven EM. We also found that IL-10, unexpectedly, induces IFN-γ production by all T cell subsets in vivo. Therefore, in addition to its established anti-inflammatory properties, IL-10 can induce IFN-γ production and EM, opening new perspectives for the design of IL-10-based immunotherapies.

2021-10-13 | GSE147195 | GEO

Interleukin-10 causes interferon γ-dependent emergency myelopoiesis

2021-10-13 | GSE172060 | GEO

Exploration of specific gene expression behind the intercellular heterogeneity of type 2 cytokine secretion activity of Group 2 innate lymphoid cell (ILC2) isolated from peripheral blood of severe asthma patients I

Project description:To investigate the gene expression underlying the intercellular diversity in type 2 cytokine secretion activity of ILC2, we performed time-series measurements of type 2 cytokine secretion activity of ILC2 from the peripheral blood of severe asthma patients after IL-33 stimulation . Single cells were collected separately before stimulation and secretion-negative or -positive cells after stimulation, and performed RNA-seq on each cell for gene expression profiling analysis.

2023-09-13 | GSE213810 | GEO

Proteome of group 2 innate lymphoid cells (ILC2s) stimulated with IL33 and TL1A

Project description:We analyzed the total proteome of group 2 innate lymphoid cells (ILC2s) after different stimulation with interleukin-33 (IL-33), a cytokine playing a critical role in human asthma, and TL1A, a TNF-family cytokine also known to activate ILC2s. Upon combined stimulation with IL-33 plus TL1A, we show that lung ILC2s produce high amounts of IL-9 and acquire a transient ‘ILC9’ phenotype. This phenotype is characterized by simultaneous production of large amounts of type 2 cytokines (IL-5, IL-13 and IL-9), induction of the IL-2 receptor CD25 (Il2ra), and of the transcription factors IRF4, JunB and BATF, that form immune-specific complexes known to induce IL-9 expression.

2024-03-05 | PXD041987 | Pride

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