Serological type I interferon promotes AIM2 inflammasome dysregulation in lupus patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE240218 | GEO | 2026/02/24
REPOSITORIES: GEO
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Project description:Serological type I interferon promotes AIM2 inflammasome dysregulation in lupus patients
| PRJNA1002995 | ENA
Project description:The innate immune system recognizes cytosolic DNA as evidence of infection, although detailed analysis is mostly limited to mice and cell lines. To investigate inflammasome responses in human primary cells, we used the inflammasome reporter caspase-1CARD-EGFP (C1C-EGFP) encoded in engineered viruses. We found that released genomes of the model poxvirus vaccinia virus (VACV) and monkeypox virus (MPXV) trigger robust inflammasome assembly in human primary cells. To determine the involved inflammasome sensors, we generated nanobodies against AIM2. Three of them inhibit AIM2 inflammasome assembly by blocking the polymerization of the AIM2 PYD, most potently as bivalent nanobodies. Utilizing VACV expressing bivalent AIM2 nanobodies, we show that inflammasomes in primary human macrophages and keratinocytes are nucleated by AIM2, while CD14+ monocytes assemble NLRP3 inflammasomes. This resolves the discrepancy between the previously reported activation of AIM2 inflammasomes in mice and NLRP3 inflammasomes in humans and provides the first evidence of cell-type-specific regulation of DNA-triggered inflammasome activation. The newly developed AIM2-specific nanobodies offer a precise tool to dissect and potentially target AIM2 inflammasome assembly in other disease contexts.
2026-01-22 | PXD069678 | Pride
Project description:Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible nuclear proteins associated with infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, a high frequency of AIM2-alterations was observed in microsatellite unstable tumors. To elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive genes by microarray. Among genes up-regulated by AIM2, there were a number of interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA) as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in ten different IFN-γ treated colorectal cancer cell lines. Moreover, knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB, and CIITA in IFN-γ treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon transient induction of AIM2. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autocrine manner. Our data indicate that AIM2 mediates IFN-γ dependent and independent induction of several Interferon stimulated genes (ISGs) including genes encoding the MHC II antigens HLA-DRα and β. we used microarray techniques to define genes responsive to AIM2 expression in colorectal tumor cells. HCT116 is a colorectal tumour cell line with no evidence for AIM2 expression which served as background for gene transfection. B8 and D1 were transfected subclones with persisting expression of AIM2. Gene expression of B8 and D1 was compared with that of mock transfected control cells.
2012-12-13 | E-GEOD-24155 | biostudies-arrayexpress
Project description:The inflammasome initiates innate defense and inflammatory response by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It is comprised of an innate immune receptor/effector, pro-caspase-1 and a common adaptor molecule, ASC (apoptotic speck-containing protein with a CARD). Consistent with their pro-inflammatory function, inflammasome components including caspase-1, ASC and NLRP3, are known to exacerbate autoimmunity during experimental autoimmune encephalomyelitis (EAE) by enhancing IL-1 and IL-18 secretion in myeloid cells3-6. Here we show an unexpected function of a DNA-binding inflammasome effector, AIM2 (Absent in Melanoma 2)7-10, in restraining autoimmunity by performing EAE in both whole body and Treg-specific deletion of Aim2–/– mice. AIM2 is highly expressed by human and mouse Treg cells and it is essential to attenuate EAE. RNA-seq, biochemical and metabolic analyses revealed that AIM2 attenuates mTOR, Myc and immune-metabolic functions in both Treg cells isolated in vivo and Treg cells induced in vitro with TGF-. Importantly, we found AIM2 physically interacted with RACK1 in Treg cells to facility the PP2A/RACK1/Akt-mTOR signaling, which is identified as a central component downstream of AIM2 that controls Treg cell function and stability. While AIM2 is generally accepted as an inflammasome effector in myeloid cells, this report reveals a previously unappreciated T cell-intrinsic role of AIM2 in maintaining Treg cell function to restrain autoimmunity. This is achieved by diminishing Akt-mTOR signaling to regulate Treg stability under inflammation, and altering immune-metabolism in Treg cells.
2021-01-27 | PXD018638 | Pride
Project description:Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain unclear. Here we found that the transcription factor IRF1 was required for the activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for AIM2 sensing depending on the pathogen encountered by the cell. We used microarrays to explore the gene expression profiles differentially expressed in Francisella-infected bone marrow-derived macrophages (BMDMs) isolated from Irf1-/-, Ifnar1-/-, Aim2-/- and wild-type mice.
2015-03-04 | E-GEOD-66461 | biostudies-arrayexpress
Project description:Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible nuclear proteins associated with infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, a high frequency of AIM2-alterations was observed in microsatellite unstable tumors. To elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive genes by microarray. Among genes up-regulated by AIM2, there were a number of interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA) as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in ten different IFN-γ treated colorectal cancer cell lines. Moreover, knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB, and CIITA in IFN-γ treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon transient induction of AIM2. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autocrine manner. Our data indicate that AIM2 mediates IFN-γ dependent and independent induction of several Interferon stimulated genes (ISGs) including genes encoding the MHC II antigens HLA-DRα and β. we used microarray techniques to define genes responsive to AIM2 expression in colorectal tumor cells.
2012-12-13 | GSE24155 | GEO
Project description:Cytoplasmic DNA triggers the activation of the innate immune system. While downstream signaling components have been characterized, the DNA sensing components remain largely elusive. We performed a systematic proteomics screen for proteins that associate with DNA, traversed to a screen for IFN-β-induced transcripts. We identified DSIRE (DNA sensor for the IL-1β response, previously called AIM2) as a candidate cytoplasmic sensor. DSIRE showed a marked selectivity for double-stranded DNA. DSIRE can recruit the inflammasome adaptor ASC and gets redistributed to ASC speckles upon coexpression of ASC. RNAi-mediated reduction of DSIRE expression led to an impairment in IL-1β maturation. Reconstitution of unresponsive cells with DSIRE, ASC, caspase 1 and IL-1β showed that DSIRE is sufficient for inflammasome activation. Overall, our data strongly suggest that DSIRE is a cytoplasmic DNA sensor for the inflammasome. In a genomic screen, we used NIH3T3, L929 and RAW264.7 cells to identify genes that were transcriptionally regulated by IFN-β. We stimulated the cells with IFN-β for 4h, isolated the RNA and analyzed global changes in gene expression by microarray analysis. Overall, 225 genes were upregulated at least 3fold, among which numerous well-known interferon-induced genes were found
2009-01-14 | E-GEOD-14413 | biostudies-arrayexpress
Project description:Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain unclear. Here we found that the transcription factor IRF1 was required for the activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for AIM2 sensing depending on the pathogen encountered by the cell.
2015-03-04 | GSE66461 | GEO
Project description:Systemic lupus erythematosus (SLE) is characterized by upregulation of Type Ι Interferon (IFN) and widespread inflammation. However, blocking the IFN pathway benefits a fraction of patients, pointing to additional pathogenic players. Here we describe monocytes (Mo) undergoing erythrophagocytosis and co-expressing IFN-inducible genes (ISGs) and interleukin-1b (IL-1b) in patients with active disease. This phenotype is recapitulated in vitro upon internalization of red blood cells carrying mitochondria (Mito+ RBCs), a feature of SLE. While ISG expression requires the interaction between Mito+ RBC-derived mitochondrial DNA (mtDNA) and cGAS, the production of IL-1b entails Mito+ RBC-derived mitochondrial RNA (mtRNA) triggering RIG-I-like receptor (RLR) activation. This leads to the cytosolic release of Mo-derived mtDNA and activation of the NLRP3 inflammasome. Importantly, the Type I IFN-inducible protein myxovirus resistant protein 1 (MxA) enables IL-1b release by routing this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. As Type I IFN and IL-1b are thought to counter-regulate each other, our study highlights an unprecedented synergy between these two cytokine pathways in SLE.
2024-10-07 | GSE211361 | GEO
Project description:Head and neck squamous cell carcinoma (HNSCC) constitutes 90% of head and neck cancers. HNSCC development is linked to chronic inflammation through mechanisms that are not fully understood. The cytosolic double-stranded DNA sensor Absent in Melanoma 2 (AIM2) is an inflammasome-forming protein that also has inflammasome-distinct roles in restricting tumorigenesis. We performed bulk RNA sequencing on tongue tissue from wild type (WT) and Aim2-/- mice treated with the carcinogen 4NQO in drinking water as a model of experimental HNSCC to uncover gene signatures regulated by AIM2 during HNSCC development.
2025-10-10 | GSE297487 | GEO