Cish attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE156967 | GEO | 2021/08/26
REPOSITORIES: GEO
Similar Datasets
Project description:Cish attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function
| PRJNA659673 | ENA
Project description:GM-CSF paradoxically possesses ability to differentiate both classically activated macrophages (MØs) with dominant proinflammatory function (M1-like MØs) and alternative activated MØs with strong immunosuppressive function (M2-like MØs). The intrinsic regulatory mechanism responsible for functional polarization of MØs under GM-CSF signalling remains elusive. Here we revealed that cytokine-inducible SH2-containing protein (CIS), induced by GM-CSF, is a key determinant in controlling MØ polarization. Compared to WT MØs, Cish-/- MØs gained characteristics of alternative activated MØs (M2 MØs), showing high expression of prototypic M2 markers Arginase 1, Tgm2 and YM-1; strong suppression of T cell proliferation; and low production of IL-12 and other proinflammatory cytokines¬¬. Differing from canonical IL-4/STAT6/IRF4 signaling axis of M2 induction, development of M2 MØ characteristics in Cish-/- MØs was associated with intensified STAT5 activation and consequent IRF8 downregulation. Attenuation of GM-CSF signalling via JAK inhibition and IRF8 rescue corrected certain functional defects in Cish-/- MØs. As CIS inhibition in NK and T cells promotes anti-tumour immunity, we showed that CIS deficiency enhanced the development of intra-tumoural M2 MØs and reduced CTL induction within tumour microenvironment with elevated GM-CSF. Overall, we conclude that CIS acts as an intrinsic rheostat to control intense GM-CSF signalling in order to maintain proinflammatory functions of MØs. Targeting CIS as a checkpoint in cancer immunotherapy should consider its role in regulating myeloid cell function.
2023-01-21 | PXD018390 | Pride
Project description:Tissue-specific cytokine stimuli orchestrate specialized homeostatic functions of resident macrophages. In the lung, steady-state signaling by the cytokine GM-CSF is critical for alveolar macrophage (AM) development and function. Here, we showed that CISH, a suppressor of cytokine signaling (SOCS) family member that is acutely induced by diverse cytokine stimuli in many tissues, was expressed constitutively in AMs in response to steady-state GM-CSF signaling. Cish deficiency led to the generation of foamy AMs and the accumulation of pulmonary surfactant. These phenotypic changes were associated with enhanced activation of STAT5, AKT, and ERK and increased expression of the gene encoding the transcription factor GATA2. RNA-seq analysis of Cish−/− AMs revealed a set of dysregulated immune and lipid-process modules, including the increased expression of genes enriched for GATA2-binding motifs. Last, Cish-deficient, bone marrow–derived macrophages showed increased Gata2 expression and accumulated more lipid upon incubation with bronchoalveolar lavage fluid compared with Cish-sufficient cells. Thus, CISH is part of a feedback loop that constrains homeostatic cytokine signaling and Gata2 expression to maintain AM identity and function.
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Project description:Cytokine–ontogeny interaction shapes macrophage transcriptional states (GM-CSF–derived macrophages)
| PRJNA1301994 | ENA
Project description:Cytokine–ontogeny interaction shapes macrophage transcriptional states (combined GM-CSF– and M-CSF–derived macrophages)
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2025-09-30 | GSE304646 | GEO
Project description:<p>Macrophages play a critical role in the inflammatory response and tumor development. Macrophages are primarily divided into pro-inflammatory M1-like and anti-inflammatory M2-like macrophages based on their activation status and functions. <em>In vitro</em> macrophage models could be derived from mouse bone marrow cells stimulated with two types of differentiation factors: GM-CSF (GM-BMDMs) and M-CSF (M-BMDMs), to represent M1-and M2-like macrophages, respectively. Since macrophage differentiation requires coordinated metabolic reprogramming and transcriptional rewiring in order to fulfill their distinct roles, we combined both transcriptome and metabolome analysis, coupled with experimental validation, to gain insight into the metabolic status of GM-and M-BMDMs. The data revealed higher levels of the tricarboxylic acid cycle (TCA cycle), oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and urea and ornithine production from arginine in GM-BMDMs, and a preference for glycolysis, fatty acid storage, bile acid metabolism, and citrulline and nitric oxide (NO) production from arginine in M-BMDMs. Correlation analysis with the proteomic data showed high consistency in the mRNA and protein levels of metabolic genes. Similar results were also obtained when compared to RNA-seq data of human monocyte derived macrophages from the GEO database. Furthermore, canonical macrophage functions such as inflammatory response and phagocytosis were tightly associated with the representative metabolic pathways. In the current study, we identified the core metabolites, metabolic genes, and functional terms of the two distinct mouse macrophage populations. We also distinguished the metabolic influences of the differentiation factors GM-CSF and M-CSF, and wish to provide valuable information for <em>in vitro</em> macrophage studies. </p>
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Project description:Dendritic cells (DC) develop from hematopoietic stem cells, which is guided by instructive signals through cytokines. DC development progresses from multipotent progenitors (MPP) via common DC progenitors (CDP) into DC. Flt3 ligand (Flt3L) signaling via the Flt3/Stat3 pathway is of pivotal importance for DC development under steady state conditions. Additional factors produced during steady state or inflammation, such as TGF-beta1 or GM-CSF, also influence the differentiation potential of MPP and CDP. Here, we studied how gp130, GM-CSF and TGF-beta1 signaling influence DC lineage commitment from MPP to CDP and further into DC. We observed that activation of gp130 signaling promotes expansion of MPP. Additionally, gp130 signaling inhibited Flt3L-driven DC differentiation, but had little effect on GM-CSF-driven DC development. The inflammatory cytokine GM-CSF induces differentiation of MPP into inflammatory DC and blocks steady state DC development. Global transcriptome analysis revealed a GM-CSF-driven gene expression repertoire that primes MPP for differentiation into inflammatory DC. Finally, TGF-beta1 induces expression of DC-lineage affiliated genes in MPP, including Flt3, Irf-4 and Irf-8. Under inflammatory conditions, however, the effect of TGF- beta1 is altered: Flt3 is not upregulated, indicating that an inflammatory environment inhibits steady state DC development. Altogether, our data indicate that distinct cytokine signals produced during steady state or inflammation have a different outcome on DC lineage commitment and differentiation. 6 samples in total. Multipotent progenitor - GM-MPP_1 - GM-MPP_2 Dendritic cell - GM-DC_1 - GM-DC_2 Dendritic cell plus TNFa - GM-TNFa-DC_1 - GM-TNFa-DC_2
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Project description:Macrophage ontogeny and local cytokines jointly govern tumor-associated macrophage behaviour, yet how these signals integrate to generate pro- or antitumor outputs is unknown. Here, we apply a reductionist, multi-scale pipeline to systematically map eight reference macrophage states generated by ex vivo differentiation of mouse bone marrow cells with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage CSF (GM-CSF) and subsequent cytokine polarization (IFN-gamma, IL-4, IL-10, TGF-beta). We integrated transcriptomic, 3D spheroid, and in vivo metastatic analyses to discover a lineage dependent polarity switch: IL-4 drives an ARG1+, tumor-supportive programme in M-CSF macrophages but, via NfkB, induces a CCR7+ inflammatory phenotype in GM-CSF macrophages. IFN-gamma uniformly activates STAT1/IRF pathways, maintaining antitumor profiles, whereas IL-10 and TGF-beta maximally evoke SPP1+ immunosuppressive signatures after GM-CSF priming. Functional assays confirmed these transcriptional states dictate opposite effects on tumor growth, invasion, and pulmonary metastasis. Integration of all parameters yielded an "ontogeny cytokine code" that predicts macrophage function based on developmental history and cytokine milieu. Identifying CSF-defined lineage as a master regulator of macrophage heterogeneity provides a blueprint for precision immunotherapies that reprogram macrophages in solid tumors. This SuperSeries is composed of the SubSeries listed below.
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