GSK3a/b restrains IFNg-inducible costimulatory molecule expression in alveolar macrophages, limiting CD4+ T cell activation
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PROVIDER: PRJNA998748 | ENA |
REPOSITORIES: ENA
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Project description:Macrophages play a crucial role in eliminating respiratory pathogens. Both pulmonary resident alveolar macrophages (AMs) and recruited macrophages contribute to detecting, responding to, and resolving infections in the lungs. Despite their distinct functions, it remains unclear how these macrophage subsets regulate their responses to infection, including how activation by the cytokine IFNg is regulated. This shortcoming prevents the development of therapeutics that effectively target distinct lung macrophage populations without exacerbating inflammation. We aimed to better understand the transcriptional regulation of resting and IFNg-activated cells using a new ex vivo model of AMs from mice, fetal liver-derived alveolar-like macrophages (FLAMs), and immortalized bone marrow-derived macrophages (iBMDMs). Our findings reveal that IFNg robustly activates both macrophage types; however, the profile of activated IFNg-stimulated genes varies greatly between these cell types. Notably, FLAMs show limited expression of costimulatory markers essential for T cell activation upon stimulation with only IFNg. To understand cell type-specific differences, we examined how the inhibition of the regulatory kinases GSK3a/b alters the IFNg response. GSK3a/b controlled distinct IFNg responses, and in AM-like cells, we found GSK3a/b restrained the induction of type I IFN and TNF, thus preventing the robust expression of costimulatory molecules and limiting CD4+ T cell activation. Together, these data suggest that the capacity of AMs to respond to IFNg is restricted in a GSK3a/b-dependent manner and that IFNg responses differ across distinct macrophage populations. These findings lay the groundwork to identify new therapeutic targets that activate protective pulmonary responses during infection without driving deleterious inflammation.
2023-08-16 | GSE239280 | GEO
Project description:Macrophages play a crucial role in eliminating respiratory pathogens. Both pulmonary resident alveolar macrophages (AMs) and recruited macrophages contribute to detecting, responding to, and resolving infections in the lungs. Despite their distinct functions, it remains unclear how these macrophage subsets regulate their responses to infection, including how activation by the cytokine IFNγ is regulated. This shortcoming prevents the development of therapeutics that effectively target distinct lung macrophage populations without exacerbating inflammation. We aimed to better understand the transcriptional regulation of resting and IFNγ-activated cells using a new ex vivo model of AMs from mice, fetal liver-derived alveolar-like macrophages (FLAMs), and immortalized bone marrow-derived macrophages (iBMDMs). Our findings reveal that IFNγ robustly activates both macrophage types; however, the profile of activated IFNγ-stimulated genes varies greatly between these cell types. Notably, FLAMs show limited expression of costimulatory markers essential for T cell activation upon stimulation with only IFNγ. To understand cell type-specific differences, we examined how the inhibition of the regulatory kinases GSK3α/β alters the IFNγ response. GSK3α/β controlled distinct IFNγ responses, and in AM-like cells, we found GSK3α/β restrained the induction of type I IFN and TNF, thus preventing the robust expression of costimulatory molecules and limiting CD4+ T cell activation. Together, these data suggest that the capacity of AMs to respond to IFNγ is restricted in a GSK3α/β-dependent manner and that IFNγ responses differ across distinct macrophage populations. These findings lay the groundwork to identify new therapeutic targets that activate protective pulmonary responses without driving deleterious inflammation.
| S-EPMC10462134 | biostudies-literature
Project description:Macrophages play a crucial role in eliminating respiratory pathogens. Both pulmonary resident alveolar macrophages (AMs) and recruited macrophages contribute to detecting, responding to, and resolving infections in the lungs. Despite their distinct functions, it remains unclear how these macrophage subsets regulate their responses to infection, including how activation by the cytokine IFN-γ is regulated. This shortcoming prevents the development of therapeutics that effectively target distinct lung macrophage populations without exacerbating inflammation. We aimed to better understand the transcriptional regulation of resting and IFN-γ-activated cells using a new ex vivo model of AMs from mice, fetal liver-derived alveolar-like macrophages (FLAMs), and immortalized bone marrow-derived macrophages. Our findings reveal that IFN-γ robustly activates both macrophage types; however, the profile of activated IFN-γ-stimulated genes varies greatly between these cell types. Notably, FLAMs show limited expression of costimulatory markers essential for T cell activation upon stimulation with only IFN-γ. To understand cell type-specific differences, we examined how the inhibition of the regulatory kinases GSK3α/β alters the IFN-γ response. GSK3α/β controlled distinct IFN-γ responses, and in AM-like cells, we found that GSK3α/β restrained the induction of type I IFN and TNF, thus preventing the robust expression of costimulatory molecules and limiting CD4+ T cell activation. Together, these data suggest that the capacity of AMs to respond to IFN-γ is restricted in a GSK3α/β-dependent manner and that IFN-γ responses differ across distinct macrophage populations. These findings lay the groundwork to identify new therapeutic targets that activate protective pulmonary responses without driving deleterious inflammation.
| S-EPMC10916365 | biostudies-literature
Project description:Gene expression studies comparing IFNg+ Tregs versus IFNg- Tregs from human peripheral blood Ex vivo sorted Tregs (CD25highCD127neg) were stimulated for 4 hours and IFNg-secreting cells were detected by a IFNg-capture kit. The samples were resorted based on IFNg expression.
2016-07-01 | E-GEOD-71274 | biostudies-arrayexpress
Project description:Gene expression studies comparing IFNg+ Tregs versus IFNg- Tregs from human peripheral blood
2016-07-01 | GSE71274 | GEO
Project description:Although well established that signal transducer and activator of transcription 1 (STAT1) activation is required for an interferon (IFN)-mediated antiviral response, the potential roles of other IFNg-activated cellular pathways in the process are unknown. We provide evidence that Unc-51-like kinase 1 (ULK1) is activated during engagement of the Type II IFN receptor and is required for IFNg-mediated transcription of key interferon stimulated genes involved in anti-viral and innate immune responses.
2018-11-20 | GSE118766 | GEO
Project description:Timecourse analysis of Interferon-Gamma (IFNg) signalling in mice deficient for IFNg or both IFNg and Suppressor of Cytokine Signalling-1 (SOCS1). Keywords: time course expression analysis
2006-02-14 | GSE4232 | GEO
Project description:Cytokine-mediated activation of host immunity is central to the control of pathogens. Interferon-gamma (IFNg) is a key cytokine in protective immunity that induces major histocompatibility complex class II molecules (MHCII) to amplify CD4+ T cell activation and effector function. Despite its central role, the dynamic regulation of IFNg-induced MHCII is not well understood. Using a genome-wide CRISPR-Cas9 screen in murine macrophages we globally identified genes that control MHCII surface expression. Mechanistic studies uncovered two parallel pathways of IFNg-mediated MHCII control that require the multifunctional glycogen synthase kinase 3 beta (GSK3b) or the mediator complex subunit MED16. Both pathways control distinct aspects of the IFNg response and are necessary for IFNg-mediated induction of the MHCII transactivator CIITA, MHCII expression, and CD4+ T cell activation. Our results define previously unappreciated regulation of MHCII expression that is required to control CD4+ T cell responses.
2021-11-01 | GSE162464 | GEO
Project description:Microarray used to detail the global gene transcription underlying sorted IFNg+ and IFNg- Tregs (CD4+CD25+CD127lo) and Tconv (CD4+CD25-CD127+) for fresh (unexpanded) and 14 day expanded cells from human blood. Treg and Tconv were FACS isolated from five healthy subjects (median age of 26, range 22-30). Sorted cells were separated into two groups: the first group was stimulated for 4 hours with PMA/ionomycin and labeled with the IFNg cytokine capture kit (Miltenyi Biotech) followed by FACS isolation of IFNg- and IFNg+ populations. The second set was expanded to day 14 prior to reactivation and cytokine cell capture. For each IFNg sorted population, cells were pelleted and flash frozen before RNA isolation and processing.
2015-05-01 | E-GEOD-59786 | biostudies-arrayexpress