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CARD9 attenuates Ab pathology and modifies microglial responses in an Alzheimer’s disease mouse model

ABSTRACT: Although significant progress in recent years has been made in defining key innate immune receptors involved in Alzheimer’s disease (AD), our knowledge of the specific intracellular signaling molecules that coordinate immune responses in AD remains poorly defined. In these studies, we have identified a previously undescribed role for the innate immune signaling molecule CARD9 in an amyloid beta (Ab)-mediated mouse model of AD. We specifically demonstrate that CARD9 deletion in the 5xFAD mouse model of AD leads to impaired control of Ab, worsened cognitive decline, and aberrant microglial activation. We further show that pharmacological activation of CARD9 provides a strategy to boost Ab clearance from the hippocampus. Collectively, these findings uncover a previously uncharacterized molecular signaling molecule used by the innate immune system in Ab-mediated neurological disease, and help to establish CARD9 as a novel molecular player that can be targeted in AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE232636 | GEO | 2023/05/23

REPOSITORIES: GEO

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Colon gene expression signatures in wild type and Card9-/-mice exposed to DSS induced colitis

Project description:It is crucial to decipher the host-microbiota interactions as they are involved in intestinal homeostasis and diseases. Caspase Recruitment Domain 9 (Card9) is an inflammatory bowel disease (IBD) susceptibility gene coding for an adapter protein for innate immunity toward many microorganisms. Card9 mediates colitis recovery via interleukin 22 pathway activation and Card9-/- mice have enhanced susceptibility to colitis. To reveal the mechanisms responsible of this defect in Card9-/-mice, we compared colon transcriptomics in WT and Card9-/- mice before and during DSS-induced colitis. Mice transcriptomes clusterized according to the genotype supporting a pattern clearly different in WT and Card9-/- mice. The number of up-regulated genes at day 7 was largely higher in Card9-/- compared to WT mice. Pathway analyses of the induced transcripts showed a dominance of immune-related pathway with a stronger signal in Card9-/- mice. Interestingly, NOD-like receptor signaling pathway, in which CARD9 is involved, was an exception with weaker activation in Card9-/- than in WT mice. During the recovery period at day 12, pathways involved in cell proliferation and replication were significantly activated in WT compared to Card9-/- mice confirming the healing defect in Card9-/- mice. For the induction of colitis, mice were given drinking water supplemented with 2% (w/v) Dextran sulphate sodium (DSS) for 7 days, then allowed to recover by drinking water alone for 5 additional days. 3 mice of each groups (WT and Card9-/-) were sacrified before DSS administration. 5 WT mice and 4 Card9-/- mice were sacrified 7 days after DSS administration and 5 mice of each group were sacrified at day 12.

2016-04-05 | E-GEOD-67577 | biostudies-arrayexpress

Effect of Card9 knockout on gene expression in cardiac tissues of mice post myocardial infarction

Project description:Immune cell infiltration in response to myocyte death contributes to extracellular matrix (ECM) remodeling and scar formation after myocardial infarction (MI). Caspase-recruitment domain protein 9 (CARD9) which belongs to CARD family acts as an adapter that mediate the transduction of proinflammatory signaling cascades in innate immunity. To investigate the role of CARD9 in cardiac injury and repair post ischemia, we subjected Card9 knockout mice to myocardial infarction (MI) , and then performed RNA-seq and gene expression profiling analysis using the ischemic cardiac tissues at 3 days post-MI, to identify key genes and pathways regulated by CARD9.

2023-10-25 | GSE235257 | GEO

CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

Project description:It is crucial to decipher the host-microbiota interactions as they are involved in intestinal homeostasis and diseases. Caspase Recruitment Domain 9 (Card9) is an inflammatory bowel disease (IBD) susceptibility gene coding for an adapter protein for innate immunity toward many microorganisms. Card9 mediates colitis recovery via interleukin 22 pathway activation and Card9-/- mice have enhanced susceptibility to colitis. To reveal the mechanisms responsible of this defect in Card9-/-mice, we compared colon transcriptomics in WT and Card9-/- mice before and during DSS-induced colitis. Mice transcriptomes clusterized according to the genotype supporting a pattern clearly different in WT and Card9-/- mice. The number of up-regulated genes at day 7 was largely higher in Card9-/- compared to WT mice. Pathway analyses of the induced transcripts showed a dominance of immune-related pathway with a stronger signal in Card9-/- mice. Interestingly, NOD-like receptor signaling pathway, in which CARD9 is involved, was an exception with weaker activation in Card9-/- than in WT mice. During the recovery period at day 12, pathways involved in cell proliferation and replication were significantly activated in WT compared to Card9-/- mice confirming the healing defect in Card9-/- mice. Results published in Nature Medicine, doi:10.1038/nm.4102

2016-04-05 | GSE67577 | GEO

Vav proteins are key regulators of Card9 signaling for innate antifungal immunity

Project description:Fungal infections are major causes of morbidity and mortality, especially in immunocompromised individuals. The innate immune system senses fungal pathogens through a family of Syk-coupled C-type lectin receptors (CLRs), which signal through the conserved immune adapter Card9. Although Card9 complexes are essential for antifungal defense in humans and mice, the mechanisms that couple CLR-proximal events to Card9 control are not well defined. Here, using a proteomic approach, we identified Vav proteins as key activators of the Card9 pathway. Vav1, Vav2 and Vav3 cooperate downstream of Dectin-1, Dectin-2 and Mincle to selectively engage Card9 for NF-κB control and proinflammatory gene transcription but are not involved in MAPK activation. Although Vav family members show functional redundancy, Vav1/2/3 triple-deficient cells are severely impaired for NF-κB and cytokine responses upon stimulation with CLR agonists or hyphae, and Vav1/2/3-/- mice phenocopy Card9-/- animals with extreme susceptibility to fungi and rapid mortality upon Candida albicans infection. In this context, Vav3 is the single most important Vav in mice, and a polymorphism in human VAV3 is associated with susceptibility to candidemia in patients. Our results reveal a molecular mechanism for CLR-mediated Card9 regulation that controls innate immunity to fungal infections.

2017-02-10 | GSE83736 | GEO

Global gene expression changes during immune complex-induced neutrophil activation (wild type and Card9‒/‒ cells)

Project description:--- Raw data of the Supplementary Table 1 of the Nature Communications article 'Neutrophil-specific deletion of the CARD9 gene expression regulator suppresses autoantibody-induced inflammation in vivo' We used microarray to obtain global gene expression data of immobilised immune complex-activated mouse neutrophils in the presence and absence of the gene expression regulator molecule CARD9.

2016-02-29 | GSE78066 | GEO

Card9 dependent activation of macrophages by TDB

Project description:Bone marrow derived macrophages from wt and card9 KO mice were stimulated with CpG, Curdlan or TDB, an analogon to the mycobacterial cord factor TDM for 48h, respectively. Keywords: card9 knockout, macropphage, TDB wt or card9 KO macrophages stimulated for 48h

2009-01-31 | E-GEOD-10530 | biostudies-arrayexpress

Genetic inhibition of CARD9 accelerates the development of experimental atherosclerosis through CD36 dependent-defective autophagy

Project description:Macrophage-mediated innate immune responses contribute to the initiation, progression and complications of atherosclerosis. However, the underlying pathways linking activation of macrophages to atherosclerotic plaque develoment are still poorly understood. We hypothesized that activation of caspase recruitment-domain containing protein 9 (CARD9) plays a determinant role in pro-atherogenic responses in macrophages. Transcriptomic analysis of human monocytes isolated from CARD9-deficient patients confirmed the pathogenic signature identified in several murine models: increased production of pro-inflammatory cytokines, improved lipid uptake, higher cell death susceptibility and defective autophagy.

2023-04-01 | GSE221782 | GEO

Card9 protects zymosan-induced peritonitis through regulating autophagy in macrophage

Project description:CARD9 is an adapter protein, which plays a critical role in anti-fungal immunity. However, the role of CARD9 in fungal-induced autophagy remains unknown. In this study, we demonstrated that Card9-/- mice displayed more severe phenotype of zymosan-induced peritonitis, presenting as multiple organs injury and increased systemic inflammation. Moreover, the number of macrophage in spleen was increased in Card9-/- mice. Further studies revealed that autophagy was impaired in peritoneal macrophages of Card9-/- -peritonitis mice. Notably, the autophagy agonist, rapamycin, ameliorated peritonitis in Card9-/- mice. Moreover, Card9 mediates the interaction of Malt1 and P62 upon zymosan stimulation. Together, our results confirmed the protective role of Card9 in the development of peritonitis via regulates autophagy in macrophage cells. The study indicates Card9 may be a potential therapeutic target for peritonitis.

2024-01-01 | GSE164572 | GEO

Cecum gene expression signatures in germ-free WT mice colonized with microbiota from WT or Card9-/- mice and infected with Citrobacter rodentium induced colitis

Project description:It is crucial to decipher the host-microbiota interactions as they are involved in intestinal homeostasis and diseases. Caspase Recruitment Domain 9 (Card9) is an inflammatory bowel disease (IBD) susceptibility gene coding for an adapter protein for innate immunity toward many microorganisms. Card9-/- mice are more susceptible to colitis induced by Citrobacter rodentium as a result of impaired of the IL-22 pathway. C. rodentium is a natural mouse pathogen widely used to model human infections with Enteropathogenic Escherichia coli and Enterohaemorrhagic E. coli. To explore the role of the gut microbiota in the susceptibility of Card9-/- mice to C. rodentium infection, we colonized WT germ-free (GF) mice with the microbiota of WT (WT-->GF) or Card9-/- (Card9-/- -->GF) mice and challenged them with C. rodentium. Card9-/- -->GF mice were more susceptible than WT-->GF mice to C. rodentium. To examine the mechanisms responsible for this defect, we compared the cecum transcriptomes of WT -->GF and Card9-/- -->GF mice before and during C. rodentium-induced colitis. The number of down-regulated and up-regulated genes on day 12 after C. rodentium infection was lower in Card9-/- -->GF mice than WT-->GF mice. Card9-/- -->GF mice showed a significant down-regulation of gut morphogenesis and wound healing pathways suggesting that recovery is impaired in Card9-/- -->GF mice after C. rodentium infection. Immune response and cell division pathways were up-regulated in WT-->GF mice but not in Card9-/- -->GF confirming the defect of global response to infection when only the Card9-/- microbiota was transferred. The most induced and differentially expressed genes between Card9-/- -->GF and WT-->GF mice on day 4 after C. rodentium infection were Reg3g (encoding REGIIIγ) and Reg3b (encoding REGIIIβ).

2017-11-25 | GSE90577 | GEO

SYK coordinates neuroprotective microglial responses in neurodegenerative disease [scRNA-seq]

Project description:Many neurodegenerative diseases are thought to be caused by impaired containment and/or disposal of neurotoxic material such as amyloid beta (Ab) and myelin debris. Indeed, recent human genome-wide association studies (GWAS) and animal model studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, as well as various innate immune receptors expressed by microglia in the control of neurotoxic material and subsequent neurodegenerative disease pathogenesis. Yet, the critical intracellular molecules that orchestrate the neuroprotective functions of microglia in degenerative disorders remain poorly understood. In our studies, we have identified the innate immune signaling molecule spleen tyrosine kinase (SYK) as a key regulator of microglial phagocytosis in neurodegenerative disease. We find that targeted deletion of SYK in microglia leads to exacerbated Ab deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Furthermore, disruption of SYK signaling in this AD model was also shown to impede the development of disease-associated microglia (DAMs), alter AKT/GSK3b-signaling in microglia, and to cause severe deficits in the ability of microglia to phagocytose Ab. Importantly, these critical neuroprotective functions of SYK in microglia were not only restricted to Ab-driven models of neurodegeneration, as we found that SYK is also a critical regulator of microglial phagocytosis and DAM phenotype acquisition in demyelinating disease. Collectively, these results help to break new ground in our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material. Moreover, these findings suggest that targeting SYK may offer a therapeutic strategy to treat a spectrum of neurodegenerative disorders.

2022-10-15 | GSE212308 | GEO

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