Interferon Signaling After TBI in Aged Mice
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ABSTRACT:
PROVIDER: PRJNA749604 | ENA |
REPOSITORIES: ENA
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Project description:Type I Interferons (IFN-I) contribute to the neuropathology of traumatic brain injury (TBI) and age-related neurodegenerative disease, where Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of Interferon Genes (STING) pathway are implicated as key inducers of IFN-I responses. This study evaluated cGAS/STING activation, IFN-I signaling and neuroinflammation in the cortex and hippocampus of young and aged C57Bl/6 male mice, 24 hrs after controlled cortical impact injury. TBI increased expression of transcripts related to IFN-I signaling and activation of cGAS in the injured cortex of aged mice compared to younger mice. These observations were confirmed by RT-PCR, western blotting and phosphorylation/activation of STAT1, a downstream IFN-I effector molecule
2021-08-20 | GSE180811 | GEO
Project description:Traumatic brain injury (TBI) is a major cause of long-term neurological impairment, with aging amplifying vulnerability and worsening recovery. Older individuals face greater cognitive and motor deficits post-TBI and respond less effectively to treatments, as both aging and TBI independently elevate neuroinflammation and cognitive decline. This study evaluated the therapeutic effects of human adipose-derived stem cell small extra-cellular vesicles (hASC-sEVs) on neurological recovery and neuroinflammation in a mouse model of TBI. Male C57BL/6 mice (3, 15, and 20 months old) underwent controlled cortical impact (CCI) and received intranasal hASC-sEVs 48 h post-injury; control groups received PBS. A dose–response study at 7 days post injury (dpi) identified 20 µg as the optimal therapeutic dose, improving motor function, reducing neuroinflammation, and enhancing neurogenesis. This was followed by a 30-dpi study assessing cognitive function, neuroinflammation, neurogenesis, and proteomic changes in microglia and astrocytes via mass spectrometry. hASC-sEV treatment significantly improved behavioral out-comes and reduced neuroinflammatory markers (GFAP, IBA-1, and MHC-II), with re-duced efficacy observed in older mice. Proteomics revealed that hASC-sEVs reduce in-flammatory proteins (TNF-α, IL-1β, IFNG, CCL2) and modulated mitochondrial dysfunction and reactive oxygen species. These results highlight hASC-sEVs as a promising cell-free therapy for improving TBI outcomes, especially in aging populations.
2025-09-11 | PXD067584 | Pride
Project description:Using 10x Genomics' single-cell RNA-seq (scRNA-seq) technology, we profiled expression of genes in cell type-specific MAGL knockout mice that received TBI. We found that there are differences in expression of genes between WT, tKO, nKO, and aKO mice in sham or TBI.
2021-06-22 | GSE178226 | GEO
Project description:Hepatocyte‑specific Ccnd1 knockout in aged mice reduces inflammatory signaling
| PRJNA1299809 | ENA
Project description:Type I interferon (IFN‑I) signaling has emerged as a central regulator of neuroinflammation across diverse central nervous system disorders, including traumatic brain injury (TBI). While TBI is a leading cause of neurologic morbidity and mortality through young adulthood, there is a paucity of neuroprotective therapies available to clinicians. Recent work has demonstrated neuroprotection after global IFN-I deficiency, yet the cell‑type‑specific contributions to traumatic brain injury (TBI) and the mechanisms of immune modulation remain poorly defined. Using mice with microglia‑specific IFN‑I receptor deficiency, we show that loss of microglial IFN‑I responsiveness suppresses microglial reactivity, reducing microglial accumulation, synaptic engulfment, antigen presentation, and T cell interactions after TBI. This attenuation preserves neuronal integrity and limits thalamic neuronal loss. However, despite this neuroprotection, microglia‑restricted IFN‑I blockade reveals functional redundancy across CNS cell types, underscoring the multi-cellular nature of IFN‑I signaling in the injured brain. Together, our findings delineate a microglial IFN‑I–dependent pathway that exacerbates secondary injury after TBI and highlight both the therapeutic potential and inherent limitations of cell‑type‑targeted IFN‑I modulation.
2026-04-23 | GSE328709 | GEO
Project description:Tissue damage precedes GvHD and the events leading up to this inflammatory disease are not well understood. To identify cell populations that may invade the intestinal tract after total body irradiation (TBI), we performed a microarray based gene expression analysis of the intestinal tract isolated from untreated mice or mice that had received 9 Gray TBI 24 h or 48 h previously. The aim of the microarray based gene expression analysis was to identify genes specific for certain cell populations that may contribute to GvHD.
2014-04-28 | E-MTAB-1566 | biostudies-arrayexpress
Project description:Neuropsychiatric complications including depression and cognitive decline develop in the years after traumatic brain injury (TBI), negatively affecting quality of life. Microglial and type 1 interferon (IFN-I) responses are associated with the transition from acute to chronic neuroinflammation after diffuse TBI in mice. Thus, the purpose of this study was to determine if impaired neuronal homeostasis and increased IFN-I responses intersected after TBI to cause cognitive impairment. Here, the RNA profile of neurons and microglia after TBI (single nucleus RNA-sequencing) with or without microglia depletion (CSF1R antagonist) was assessed 7 dpi. There was a TBI-dependent suppression of cortical neuronal homeostasis with reductions in CREB signaling, synaptogenesis, and synaptic migration and increases in RhoGDI and PTEN signaling (Ingenuity Pathway Analysis). Microglial depletion reversed 50% of TBI-induced gene changes in cortical neurons depending on subtype. Moreover, the microglial RNA signature 7 dpi was associated with increased stimulator of interferon genes (STING) activation and IFN-I responses. Therefore, we sought to reduce IFN-I signaling after TBI using STING knockout mice and a STING antagonist, chloroquine (CQ). TBI-associated cognitive deficits in novel object location and recognition (NOL/NOR) tasks at 7 and 30 dpi were STING dependent. In addition, TBI-induced STING expression, microglial morphological restructuring, inflammatory (Tnf, Cd68, Ccl2) and IFN-related (Irf3, Irf7, Ifi27) gene expression in the cortex were attenuated in STINGKO mice. CQ also reversed TBI-induced cognitive deficits and reduced TBI-induced inflammatory (Tnf, Cd68, Ccl2) and IFN (Irf7, Sting) cortical gene expression. Collectively, reducing IFN-I signaling after TBI with STING-dependent interventions attenuated the prolonged microglial activation and cognitive impairment.
2025-06-05 | GSE299005 | GEO
Project description:Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of “precarious balance”, due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.
2025-10-14 | GSE279751 | GEO
Project description:Patients aged 65 years and older account for an increasing proportion of those who suffer from traumatic brain injury (TBI). Aged TBI patients experience increased morbidity and mortality compared to young TBI patients. Our prior data demonstrated that anti-CD49d antibody (aCD49d Ab), an FDA-approved drug that blocks α4 integrin, abrogates infiltration of CD8+ T-cells into the injured brain, improves survival, and attenuates neurocognitive deficits. Yet, the molecular mechanisms underlying the therapeutic effects of aCD49d Ab remained unexplored. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, we found that mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of CD8+ T cell cytotoxicity. Further, aCD49d Ab further produces a neuroprotective Th2 response and restores age-associated CD8+ T cell senescence. Our results demonstrate that targeting infiltrating CD8+ T cells with aCD49d Ab is a promising therapeutic strategy for treating TBI in aged individuals.
2024-10-23 | GSE260719 | GEO
Project description:Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of “precarious balance”, due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.
2026-05-01 | GSE313885 | GEO