TFAM deficiency promotes mitochondrial dysfunction to drive inflammation in the corneas of dry eye disease through mtDNA stress-mediated AIM2 inflammasome activation
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PROVIDER: PRJNA1063432 | ENA |
REPOSITORIES: ENA
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Project description:Background & Aims Mitochondrial dysfunction and mtDNA stress-mediated inflammasome activation play critical roles in the pathogenesis of dry eye disease (DED). Mitochondrial transcription factor A (TFAM) is essential for regulating mtDNA stability and mitochondrial homeostasis. However, the mechanism underling TFAM to infuence DED progression is largely unknown. As a cytosolic DNA sensor, absent in melanoma 2 (AIM2) may contribute to the development of DED. Therefore, we aimed to explore whether the role of TFAM is associated with AIM2 inflammasome activation in DED. Methods The changes in inflammation, mitochondrial function, mtDNA homeostasis and TFAM expression were analyzed in the corneas of DED mice in vivo and in HCECs under oxidative stress in vitro. The effects of TFAM knockout on mtDNA homeostasis, mitochondrial respiration and cytokine release were also investigated in HCECs. The mechanism was analyzed by RNA sequencing in the corneas of DED mice, which was further verified by the HCECs with TFAM depletion. Results We found that the corneas of DED mice and HCECs under oxidative stress exhibited inflammation, mitochondrial damage and mtDNA maintenance disruption , which were highly associated with significantly reduced TFAM protein levels. Furthermore, we demonstrated that silencing of TFAM in HCECs suppressed mitochondrial respiratory capacity, induced mtDNA released into the cytosol and triggered cytokine release. Mechanistically, cytosolic mtDNA accumulation caused by TFAM depletion activated the AIM2 inflammasome and facilitated inflammation, thereby driving DED progression. Conclusions Our findings elucidate that TFAM deficiency induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the AIM2 inflammasome, triggers inflammatory responses and promotes DED progression. TFAM pathway may provide a novel therapeutic strategy for DED.
2024-06-18 | GSE252984 | GEO
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: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: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:The spatial organization of gut microbiome is essential for their interactions with the host. Recently, microbiota alteration in ileum is getting the increasing recognition due to the close interplay with inflammatory diseases and the tumor immunosurveillance. However, how ileal microbiome is spatially regulated remains unclear. Here, we show that DNA-damaging chemotherapy specifically remodels microbiota in ileal mucosa, resulting in the overgrowth of local family Lachnospiraceae that promotes antitumor immunity and synergizes with immune checkpoint blockage. Mechanistically, the prominent proliferative state of transit amplifying cells (TACs) in the ileal crypt presents a vulnerability to chemotherapy-caused genomic stress, resulting in the accumulation of cytosolic dsDNA that subsequently activates AIM2 inflammasome. AIM2-dependent production of IL18 boosts Th1 immunity in ileal lamina propria, which further impairs the antimicrobial host defense of proximal Paneth cells via activating IFN-γ-JAK-STAT signaling. Our findings demonstrate that AIM2 inflammasome shapes ileal microbiome via governing the compartmentalized cellular interplay in ileal crypt, providing mechanistic insights into the regulation of gut biogeography and implicating therapeutic strategies of spatial microbiome intervention using chemotherapy.
2024-03-12 | GSE168793 | GEO
Project description:Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune receptor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators were largely intact in Aim2-deficient mice, however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with wild-type healthy mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer. We used microarrays to compare the transcriptome Aim2 deficent mice to wild type mice in colon tumor and colitis samples. Here were 12 mice in total, 3 for each genotype and tissue combination.
2015-07-15 | E-GEOD-69436 | biostudies-arrayexpress
Project description:Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune receptor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators were largely intact in Aim2-deficient mice, however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with wild-type healthy mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.
2015-07-15 | GSE69436 | GEO
Project description:Absent in melanoma 2 (AIM2) is a cytosolic dsDNA sensor that has been broadly studied for its role in inflammasome assembly and innate immune defense against intracellular pathogens. However, very little is known about the function of AIM2 in adaptive immune cells. The purpose of this study was to investigate whether AIM2 has a cell-intrinsic role in CD4+ T cell differentiation or function. We found that AIM2 is expressed in both human and mouse CD4+ T cells and that its expression is affected by T cell receptor (TCR) activation. AIM2-deficient (Aim2-/-) mouse CD4+ T cells upregulate the expression of regulatory T cell (Treg)-associated genes, both in unstimulated conditions and after TCR activation. Naïve CD4+ T cells from Aim2-/- mice also show a higher tendency to differentiate into FOXP3+ cells in vitro, while their capacity to differentiate into Th1 or Th17 cells remains unaltered. In agreement with these data, in a T cell transfer model of colitis, Aim2-/- naïve T cells induce ameliorated disease and also display a higher ability to differentiate into FOXP3+ cells. Our results suggest that AIM2 negatively regulates FOXP3 expression and Treg cell differentiation. We show that AIM2 function is not confined to innate immune cells but is also important in adaptive CD4+ T cells. Our data identify AIM2 as a regulator of Treg cell differentiation and therefore as a potential intervention target for restoring T cell homeostasis.
2023-05-26 | GSE151782 | GEO
Project description:Absent in melanoma 2 (AIM2) is a cytosolic dsDNA sensor that has been broadly studied for its role in inflammasome assembly. However, little is known about the function of AIM2 in adaptive immune cells. The purpose of this study was to investigate whether AIM2 has a cell-intrinsic role in CD4+ T cell differentiation or function. We found that AIM2 is expressed in both human and mouse CD4+ T cells and that its expression is affected by T cell receptor (TCR) activation. Naïve CD4+ T cells from AIM2-deficient (Aim2-/-) mice showed higher ability to maintain forkhead box P3 (FOXP3) expression in vitro, while their capacity to differentiate into T helper (Th)1, Th2 or Th17 cells remained unaltered. Transcriptional profiling by RNA sequencing showed that AIM2 might affect regulatory T cell (Treg) stability not by controlling the expression of Treg signature genes, but through the regulation of the cell's metabolism. In addition, in a T cell transfer model of colitis, Aim2-/--naïve T cells induced less severe body weight loss and displayed a higher ability to differentiate into FOXP3+ cells in vivo. In conclusion, we show that AIM2 function is not confined to innate immune cells but is also important in CD4+ T cells. Our data identify AIM2 as a regulator of FOXP3+ Treg cell differentiation and as a potential intervention target for restoring T cell homeostasis.
2022-05-27 | GSE184479 | GEO
Project description:Ednrb is specifically required to develop neural crest (NC) stem cell-derived lineages. However, it is still unknown why Ednrb signaling is only needed for the early development of melanoblasts in the skin and eye. We show that Ednrb is required for the proliferation of melanoblasts during early mouse development. To understand the mechanism of melanoblast proliferation, we found that the gene absent in melanoma 2 (Aim2) is upregulated in Ednrb-deficient NC cells by RNA-sequencing analysis. Consequently, the knockdown or knockout of Aim2 partially rescued the proliferation of Ednrb-deficient melanoblasts. Conversely, the overexpression of Aim2 in melanoblasts suppressed their proliferation. We further show that Ednrb signaling could act through the microRNA miR-196b to block the suppression of melanoblast proliferation by Aim2 in primary NC cell cultures. These results reveal the Ednrb–Aim2–AKT axis in regulating melanocyte development and suggest that Ednrb signaling functions as a negative regulator of Aim2, which inhibits the proliferation of melanoblasts in early development. These findings uncover a previously unreported role for Aim2 outside the inflammasome, showing that it is a significant regulator controlling NC stem cell-derived lineage development.
2024-11-06 | GSE275956 | GEO