Donor bone marrow-derived macrophage MHC II drives neuroinflammation and cognitive deficits during chronic GVHD in mice
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PROVIDER: PRJNA743850 | ENA |
REPOSITORIES: ENA
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Project description:Graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality after allogeneic stem cell transplantation for haematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients, however, the mechanisms driving chronic GVHD in the CNS are yet to be elucidated. Our studies of murine chronic GVHD revealed a spatial learning and memory deficit associated with inflammation in the hippocampus underlain by persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the chronic GVHD brain from early CD8 dominance to later CD4 sequestration. Hippocampal RNA sequencing identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with IFN-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived TNF. In contrast, infiltration of pro-inflammatory MHC class II+ donor bone marrow-derived macrophages (BMDM) was identified as a distinguishing feature of CNS chronic GVHD. Donor BMDM, which comprised up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout bone marrow grafts exhibited attenuated neuroinflammation, suggestive of a critical role for donor BMDM in chronic CNS GVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.
2021-08-18 | GSE179441 | GEO
Project description:It is important to maintain cognitive integrity during underwater operations, which may also trigger cognitive alterations. Cognitive effect of underwater operations and the underlying mechanism remain elusive. Here, we found a single underwater operation affects cognition in a time-dependent model. Prolonged exposure elicits significant cognitive impairment and hippocampal dysfunction, which was accompanied by activation of microglia and upregulation of pro-inflammatory cytokines. RNA-sequencing supported the involvement of neuroinflammation and indicated the critical role of CCR3. Knockdown of CCR3 significantly rescued cognitive impairment and hippocampal dysfunction. Furthermore, the upregulation of pro-inflammatory cytokines was also reversed. Mechanistically, CCR3 knockdown switched the activated microglia from a pro-inflammatory to neuroprotective phenotype. Taken together, these results highlighted the time-dependent effects of a single underwater operation on cognitive function. Knocking down CCR3 can attenuate neuroinflammation by regulating polarization of activated microglia, thereby alleviating prolonged underwater operation-induced cognitive impairment.
2024-05-20 | GSE247651 | GEO
Project description:Type 2 diabetes (T2D) is associated with increased risk of cognitive decline although the precise underlying pathogenesis remains obscure. Based on the single-cell RNA sequencing approach applied to the cerebral cortex of a T2D mouse model (db/db), we identified novel regulatory mechanisms underlying diabetes-associated cognitive deficits. Our data adds detail to the highly complex neurovascular pathology associated with T2D and highlights key cell-specific deficits in mitochondrial bioenergetics linked to neuroinflammation, which underlie T2D-linked cognitive impairment.
2023-06-26 | GSE217665 | GEO
Project description:Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. Here, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old wildtype mice, and in a mouse model of tauopathy. We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and tauopathy mice. These effects of NF-κB/NLRP3-targeting Nanoligomer treatment were associated with reduced glial cell activation in old wildtype mice, less pathology in tauopathy mice, favorable changes in transcriptome signatures of inflammation (reduced) and neuronal health (increased) in both mouse models, and no adverse systemic effects. Collectively, our results provide a basis for future translational studies targeting NF-κB/NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegenerative disease.
2024-02-07 | GSE251888 | GEO
Project description:Background: Age-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruption’s well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleep’s relationship to cognitive aging. Methodology: We measured sleep stages in young adult and aged F344 rats during inactive (enhanced sleep) and active (enhanced wake) periods. Animals were behaviorally characterized on the Morris water maze and gene expression profiles of their parietal cortices were taken. Principal Findings: Water maze performance was impaired, and inactive period deep sleep was decreased with age. However, increased deep sleep during the active period was most strongly correlated to maze performance. Transcriptional profiles were strongly associated with behavior and age, and were validated against prior studies. Bioinformatic analysis revealed increased translation and decreased myelin/ neuronal pathways. Conclusions: The F344 rat appears to serve as a reasonable model for some common sleep architecture and cognitive changes seen with age in humans, including the cognitively disrupting influence of active period deep sleep. Microarray analysis suggests that the processes engaged by this sleep are consistent with its function. Thus, active period deep sleep appears temporally misaligned but mechanistically intact, leading to the following: first, aged brain tissue appears capable of generating the slow waves necessary for deep sleep, albeit at a weaker intensity than in young. Second, this activity, presented during the active period, seems disruptive rather than beneficial to cognition. Third, this active period deep sleep may be a cognitively pathologic attempt to recover age-related loss of inactive period deep sleep. Finally, therapeutic strategies aimed at reducing active period deep sleep (e.g., by promoting active period wakefulness and/or inactive period deep sleep) may be highly relevant to cognitive function in the aging community. KEYWORDS: frontal cortex, rat, young or aged We implanted young and aged Fischer 344 rats (n = 6/ group) with wireless EEG, EMG and movement monitoring devices to measure sleep architecture. Animals were trained in the Morris water maze to assess cognitive function, and frontal cortices were removed for microarray analysis.sleep disruption and cognitive decline.
2011-04-21 | E-GEOD-24515 | biostudies-arrayexpress
Project description:Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognised, where brain-infiltrating donor MHC class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesised that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early post-transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients where CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signalling post-transplant failed to reverse GVHD-induced behavioural changes. Moreover, we observed aberrant behaviour in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.
2023-10-18 | GSE245360 | GEO
Project description:In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), severe graft-versus-host disease (GVHD) is tied to failed donor plasmacytoid DC (pDC) reconstitution. The mechanism whereby GVHD causes donor pDC defects and the precise role donor pDCs play in GVHD remain poorly understood. pDCs develop from HSCs in successive stages through Flt3 signaling-dependent differentiation, beginning as multi-potent progenitors (MPPs) and later becoming common DC progenitors. We observed that MPPs were critical for sustaining pDCs and were severely depleted during GVHD. Loss of MPPs was associated with decreased amounts of MPP-producing HSCs and mTOR activation-induced cell death of proliferating MPPs. Additionally, GM-CSF derived from alloreactive T cells subverted MPP production of pDCs. Together, GVHD and alloreactive T cells caused donor pDC defects by impairing the generation, maintenance and differentiation of HSCs and MPPs. Importantly, pDCs suppressed the proliferation and expansion of activated autologous CD4+ T cells via a type I-IFN signaling-dependent mechanism. Transfer of donor pDCs early after transplantation repressed GVHD and preserved potent GVL effects, significantly improving the survival of leukemia mice undergoing allo-HSCT. Our findings identify novel strategies that improve the recovery of donor pDCs early after allo-HSCT and thus may represent an effective therapy to control GVHD. Our findings have broad implications for other diseases in which functional DC development is impaired, such as chronic infections, autoimmunity and cancer.
2021-01-06 | GSE143788 | GEO
Project description:Pathological FUS inclusions are found in 10% of patients with frontotemporal dementia (FTD) and those with amyotrophic lateral sclerosis (ALS) carrying FUS mutations. Current work indicates that FUS mutations may incur gain-of-toxic functions to drive ALS pathogenesis. However, how FUS dysfunction may affect cognition remains elusive. Using a mouse model expressing wild-type human FUS mimicking the endogenous expression pattern and level within the central nervous system, we found that they developed hippocampus-mediated cognitive deficits accompanied by an age-dependent reduction in spine density and long-term potentiation (LTP) in their hippocampus. However, there were no apparent FUS aggregates, nuclear envelope defects and cytosolic FUS accumulation. These suggest that these proposed pathogenic mechanisms may not be the underlying causes for the observed cognitive deficits. Unbiased transcriptomic analysis identified expression changes in a small set of genes with preferential expression in the neurons and oligodendrocyte lineage cells. Of these, we focused on Sema5a, a gene involved in axon guidance, spine dynamics, Parkinson’s disease and autism spectrum disorders. Critically, FUS binds directly to Sema5a mRNA and regulates Sema5a expression in a FUS-dose-dependent manner. Taken together, our data suggest that FUS-driven Sema5a deregulation may underlie the cognitive deficits in FUS transgenic mice.
2020-07-30 | GSE135075 | GEO
Project description:Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduced neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
2024-05-13 | GSE252964 | GEO
Project description:Neuroinflammation is a common feature of neurodegenerative disorders such as Alzheimer's disease (AD). Neuroinflammation is induced by dysregulated glial activation, and astrocytes, the most abundant glial cells, become reactive upon neuroinflammatory cytokines released from microglia, and actively contribute to neuronal loss. Therefore, blocking reactive astrocyte functions is a viable strategy to manage neurodegenerative disorders. However, factors or therapeutics directly regulating astrocyte subtype remain unexplored. Here, we identified transcription factor NF-E2-related factor 2 (Nrf2) as a therapeutic target in neurotoxic reactive astrocytes upon neuroinflammation. We found that the absence of Nrf2 promoted the activation of reactive astrocytes in the brain tissue samples obtained from AD model 5xFAD mice, whereas enhanced Nrf2 expression blocked the induction of reactive astrocyte gene expression by counteracting NF-kB subunit p65 recruitment. Neuroinflammatory astrocytes robustly upregulated genes associated with type I interferon and the antigen-presenting pathway, which were suppressed by Nrf2 pathway activation. Moreover, impaired cognitive behaviors observed in AD mice were rescued upon ALGERNON2 treatment, which potentiated Nrf2 pathway and reduced the induction of neurotoxic reactive astrocytes. Thus, we highlight the potential of astrocyte-targeting therapy by promoting the Nrf2 pathway signaling for neuroinflammation-triggered neurodegeneration.
2023-08-07 | GSE237423 | GEO