Article

Yeretssian, G. et al. Non-apoptotic role of BID in inflammation and innate immunity. Nature 474, 96-99

Department of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada.
Nature (Impact Factor: 41.46). 06/2011; 474(7349):96-9. DOI: 10.1038/nature09982
Source: PubMed

ABSTRACT

Innate immunity is a fundamental defence response that depends on evolutionarily conserved pattern recognition receptors for sensing infections or danger signals. Nucleotide-binding and oligomerization domain (NOD) proteins are cytosolic pattern-recognition receptors of paramount importance in the intestine, and their dysregulation is associated with inflammatory bowel disease. They sense peptidoglycans from commensal microorganisms and pathogens and coordinate signalling events that culminate in the induction of inflammation and anti-microbial responses. However, the signalling mechanisms involved in this process are not fully understood. Here, using genome-wide RNA interference, we identify candidate genes that modulate the NOD1 inflammatory response in intestinal epithelial cells. Our results reveal a significant crosstalk between innate immunity and apoptosis and identify BID, a BCL2 family protein, as a critical component of the inflammatory response. Colonocytes depleted of BID or macrophages from Bid(-/-) mice are markedly defective in cytokine production in response to NOD activation. Furthermore, Bid(-/-) mice are unresponsive to local or systemic exposure to NOD agonists or their protective effect in experimental colitis. Mechanistically, BID interacts with NOD1, NOD2 and the IκB kinase (IKK) complex, impacting NF-κB and extracellular signal-regulated kinase (ERK) signalling. Our results define a novel role of BID in inflammation and immunity independent of its apoptotic function, furthering the mounting evidence of evolutionary conservation between the mechanisms of apoptosis and immunity.

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Available from: Ricardo G Correa, Sep 03, 2014
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    • "The differences in a potential BID involvement in ischemic neuronal injury may therefore be a consequence of differences in excitotoxic and/or inflammatory signaling between the different models employed. As it has previously been shown that BID affects the inflammatory response both in vitro, and in vivo (Scatizzi et al., 2007; Chung et al., 2010; Mayo et al., 2011; Yeretssian et al., 2011; König et al., 2014), we therefore chose to look at microglial/leukocyte activation in our model. Microglial cells are known to contribute substantially to the elevation of cytokine levels in the brain after focal cerebral ischemia (Lambertsen et al., 2012) and the lack of IBA1 microglial/leukocyte activation or recruitment in the ipsilateral hemisphere in BID-KO mice observed in the present study may be responsible for a lower levels of proinflammatory cytokines in BID-KO mice. "

    Full-text · Dataset · Feb 2016
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    • "The differences in a potential BID involvement in ischemic neuronal injury may therefore be a consequence of differences in excitotoxic and/or inflammatory signaling between the different models employed. As it has previously been shown that BID affects the inflammatory response both in vitro, and in vivo (Scatizzi et al., 2007; Chung et al., 2010; Mayo et al., 2011; Yeretssian et al., 2011; König et al., 2014), we therefore chose to look at microglial/leukocyte activation in our model. Microglial cells are known to contribute substantially to the elevation of cytokine levels in the brain after focal cerebral ischemia (Lambertsen et al., 2012) and the lack of IBA1 microglial/leukocyte activation or recruitment in the ipsilateral hemisphere in BID-KO mice observed in the present study may be responsible for a lower levels of proinflammatory cytokines in BID-KO mice. "
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    ABSTRACT: The BH3 interacting-domain death agonist (BID) is a pro-apoptotic protein involved in death receptor-induced and mitochondria-mediated apoptosis. Recently, it has also been suggested that BID is involved in the regulation of inflammatory responses in the central nervous system. We found that BID deficiency protected organotypic hippocampal slice cultures in vitro from neuronal injury induced by oxygen-glucose deprivation. In vivo, BID-knockout (KO) mice and WT mice were subjected to 60 minutes of transient middle cerebral artery occlusion to induce focal cerebral ischemia, and allowed to recover for 24 hours. Infarct volumes and functional outcome were assessed and the inflammatory response was evaluated using immunofluorescence, Western blotting, quantitative PCR and Mesoscale multiplex analysis. We observed no difference in the infarct volume or neurological outcome between BID-KO and WT mice. The inflammatory response was reduced by BID deficiency as indicated by a change in microglial/leukocyte response. In conclusion, our data suggest that BID deficiency is neuroprotective in an in vitro model and modulates the inflammatory response to focal cerebral ischemia in vivo. However, this is not translated into a robust neuroprotection in vivo.
    Full-text · Article · Jan 2016 · Frontiers in Cellular Neuroscience
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    • "Interestingly, the suppression of pathologically elevated NF-κB activity has repeatedly been linked to improved outcome in CNS injury (Brambilla et al., 2009), sciatic nerve injury and ALS (Fu et al., 2010; Otsmane et al., 2013). A 'non-apoptotic' function of Bid may be in accordance with previous studies that demonstrated a direct influence of Bid on NF-κB activity (Luo et al., 2010; Yeretssian et al., 2011). The latter study suggested a biological link between the NOD1 (nucleotide-binding oligomerization domain containing 1) signalosome and Bid in intestinal epithelial cells, evidenced by coimmunoprecipitation between Bid protein, components of the inflammasome and the IκB kinase (IKK)-complex, and a marked deficiency of bid deficient cells to phosphorylate the canonical IKK target protein, IκBα. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons in the spinal cord, brainstem and motor cortex. Mutations in the superoxide dismutase 1 (SOD1) gene represent a frequent genetic determinant and recapitulate a disease phenotype similar to ALS when expressed in mice. Previous studies using SOD1(G93A) transgenic mice have suggested a paracrine mechanism of neuronal loss, in which cytokines and other toxic factors released from astroglia or microglia trigger motoneuron degeneration. Several pro-inflammatory cytokines activate death receptors and may downstream from this activate the Bcl-2 family protein, Bid. We here sought to investigate the role of Bid in astrocyte activation and non-cell autonomous motoneuron degeneration. We found that spinal cord Bid protein levels increased significantly during disease progression in SOD1(G93A) mice. Subsequent experiments in vitro indicated that Bid was expressed at relatively low levels in motoneurons, but was enriched in astrocytes and microglia. Bid was strongly induced in astrocytes in response to pro-inflammatory cytokines or exposure to lipopolysaccharide. Experiments in bid-deficient astrocytes or astrocytes treated with a small molecule Bid inhibitor demonstrated that Bid was required for the efficient activation of transcription factor nuclear factor-κB in response to these pro-inflammatory stimuli. Finally, we found that conditioned medium from wild-type astrocytes, but not from bid-deficient astrocytes, was toxic when applied to primary motoneuron cultures. Collectively, our data demonstrate a new role for the Bcl-2 family protein Bid as a mediator of astrocyte activation during neuroinflammation, and suggest that Bid activation may contribute to non-cell autonomous motoneuron degeneration in ALS.
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