Microglial p53 activation is detrimental to neuronal synapses during activation-induced inflammation: Implications for neurodegeneration

Jebelli, Joseph; Hooper, Claudie; Pocock, Jennifer M.

doi:10.1016/j.neulet.2014.08.049

Cited by 40 publications

(31 citation statements)

References 29 publications

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“…Emerging evidence suggests broader roles of p53 in interacting with the inflammatory pathway by modulating glial function and promoting NF-κB transcription [11, 32, 33]. For example, microglial secretion of the inflammatory cytokines IL-1β and TNF-α was demonstrated to be p53-dependent in neurodegenerative diseases, whereas the inhibition of p53 by PFT-α reversed the above proinflammatory phenotypic change in microglial cells [32]. Consistent with this observation, our double immunofluorescence staining confirmed that increased p53 and PUMA fluorescent labels were also widely distributed in activated astrocytes (displayed as hypertrophic body size) and microglial cells (displayed as amoeboid morphology).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Chen

et al. 2018

J Neuroinflammation

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BackgroundIschaemia reperfusion (IR) induces multiple pathophysiological changes. In addition to its classical role in regulating tumourigenesis, the feedback loop formed by p53 and its driven target p53-upregulated modulator of apoptosis (PUMA) was recently demonstrated to be the common node tightly controlling various cellular responses during myocardial IR. However, the roles of the p53-PUMA feedback loop in the spinal cord remain unclear. This study aimed to elucidate the roles of p53-PUMA feedback interactions in the spinal cord after IR, specifically investigating their regulation of caspase 3-mediated apoptosis and nuclear factor (NF)-κB-mediated cytokine release.MethodsSD rats subjected to 12 min of aortic arch occlusion served as IR models. Neurological assessment as well as p53 and PUMA mRNA and protein expression analyses were performed at 12-h intervals during a 48-h reperfusion period. The cellular distributions of p53 and PUMA were determined via double immunofluorescence staining. The effects of the p53-PUMA feedback loop on modulating hind-limb function; the number of TUNEL-positive cells; and protein levels of caspase 3, NF-κB and cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α, were evaluated by intrathecal treatment with PUMA-specific or scramble siRNA and pifithrin (PFT)-α. Blood-spinal cord barrier (BSCB) breakdown was examined by Evans blue (EB) extravasation and water content analyses.ResultsIR induced significant behavioural deficits as demonstrated by deceased Tarlov scores, which displayed trends opposite those of PUMA and p53 protein and mRNA expression. Upregulated PUMA and p53 fluorescent labels were widely distributed in neurons, astrocytes and microglia. Injecting si-PUMA and PFT-α exerted significant anti-apoptosis effects as shown by the reduced number of TUNEL-positive cells, nuclear abnormalities and cleaved caspase 3 levels at 48 h post-IR. Additionally, p53 colocalized with NF-κB within the cell. Similarly, injecting si-PUMA and PFT-α exerted anti-inflammatory effects as shown by the decreased NF-κB translocation and release of IL-1β and TNF-α. Additionally, injecting si-PUMA and PFT-α preserved the BSCB integrity as determined by decreased EB extravasation and spinal water content. However, injecting si-Con did not induce any of the abovementioned effects.ConclusionsInhibition of aberrant p53-PUMA feedback loop activation by intrathecal treatment with si-PUMA and PFT-α prevented IR-induced neuroapoptosis, inflammatory responses and BSCB breakdown by inactivating caspase 3-mediated apoptosis and NF-κB-mediated cytokine release.

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Section: Discussionmentioning

confidence: 99%

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Chen

et al. 2018

J Neuroinflammation

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“…In Figure 3B, as in A, no changes in astrocyte density and morphology were seen; however, a loss in contaminating microglial number and reactivity was observed. For a brief description of the immunocytochemistry (ICC) protocol used in this manuscript, please see reference 11 . Figure 1: Characterization of LME treatment of CGCs.…”

Section: Representative Resultsmentioning

confidence: 99%

Selective Depletion of Microglia from Cerebellar Granule Cell Cultures Using L-leucine Methyl Ester

Jebelli

Piers

Pocock

2015

JoVE

Self Cite

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Microglia, the resident immunocompetent cells of the CNS, play multifaceted roles in modulating and controlling neuronal function, as well as mediating innate immunity. Primary rodent cell culture models have greatly advanced our understanding of neuronal-glial interactions, but only recently have methods to specifically eliminate microglia from mixed cultures been utilized. One such technique -described here -is the use of L-leucine methyl ester, a lysomotropic agent that is internalized by macrophages and microglia, wherein it causes lysosomal disruption and subsequent apoptosis 13,14 . Experiments using L-leucine methyl ester have the power to identify the contribution of microglia to the surrounding cellular environment under diverse culture conditions. Using a protocol optimized in our laboratory, we describe how to eliminate microglia from P5 rodent cerebellar granule cell culture. This approach allows one to assess the relative impact of microglia on experimental data, as well as determine whether microglia are playing a neuroprotective or neurotoxic role in culture models of neurological conditions, such as stroke, Alzheimer's or Parkinson's disease. Video LinkThe video component of this article can be found at

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“…HIV-infected p53-deficient neuron/microglia cocultures showed increased neuronal survival compared with WT (78). Microglial p53 activation is detrimental to neuronal synapses during inflammation (82). P53 -/-microglia had lower expression of proinflammatory genes and demonstrated increased phagocytosis and expression of tissue support genes in response to IFN-γ (81).…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 99%

Transcriptional control of microglia phenotypes in health and disease

Holtman¹,

Skola²,

Glass³

2017

Journal of Clinical Investigation

175

156

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Microglial p53 activation is detrimental to neuronal synapses during activation-induced inflammation: Implications for neurodegeneration

Cited by 40 publications

References 29 publications

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Selective Depletion of Microglia from Cerebellar Granule Cell Cultures Using L-leucine Methyl Ester

Transcriptional control of microglia phenotypes in health and disease

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