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Marie GLEIZES




4 publication(s) depuis Janvier 2017:


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04/2020 | bone
Tissue-nonspecific alkaline phosphatase is an anti-inflammatory nucleotidase.
Bessueille L, Briolay A, Como J, Mebarek S, Mansouri C, Gleizes M, El Jamal A, Buchet R, Dumontet C, Matera E, Mornet E, Millan J, Fonta C, Magne D

Abstract:
Tissue-nonspecific alkaline phosphatase (TNAP) is necessary for skeletal mineralization by its ability to hydrolyze the mineralization inhibitor inorganic pyrophosphate (PPi), which is mainly generated from extracellular ATP by ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Since children with TNAP deficiency develop bone metaphyseal auto-inflammations in addition to rickets, we hypothesized that TNAP also exerts anti-inflammatory effects relying on the hydrolysis of pro-inflammatory adenosine nucleotides into the anti-inflammatory adenosine. We explored this hypothesis in bone metaphyses of 7-day-old Alpl+/? mice (encoding TNAP), in mineralizing hypertrophic chondrocytes and osteoblasts, and non-mineralizing mesenchymal stem cells (MSCs) and neutrophils, which express TNAP and are present, or can be recruited in the metaphysis. Bone metaphyses of 7-day-old Alpl+/? mice had significantly increased levels of Il-1? and Il-6 and decreased levels of the anti-inflammatory Il-10 cytokine as compared with Alpl+/+ mice. In bone metaphyses, murine hypertrophic chondrocytes and osteoblasts, Alpl mRNA levels were much higher than those of the adenosine nucleotidases Npp1, Cd39 and Cd73. In hypertrophic chondrocytes, inhibition of TNAP with 25 ?M of MLS-0038949 decreased the hydrolysis of AMP and ATP. However, TNAP inhibition did not significantly modulate ATP- and adenosine-associated effects in these cells. We observed that part of TNAP proteins in hypertrophic chondrocytes was sent from the cell membrane to matrix vesicles, which may explain why TNAP participated in the hydrolysis of ATP but did not significantly modulate its autocrine pro-inflammatory effects. In MSCs, TNAP did not participate in ATP hydrolysis nor in secretion of inflammatory mediators. In contrast, in neutrophils, TNAP inhibition with MLS-0038949 significantly exacerbated ATP-associated activation and secretion of IL-1?, and extended cell survival. Collectively, these results demonstrate that TNAP is a nucleotidase in both hypertrophic chondrocytes and neutrophils, and that this nucleotidase function is associated with autocrine effects on inflammation only in neutrophils.




02/2019 | physiol rep
Effect of adenosine on short?term synaptic plasticity in mouse piriform cortex in
Perrier SP, Gleizes M, Fonta C, Nowak LG

Abstract:
We examined the effect of adenosine and of adenosine A1 receptor blockage on short?term synaptic plasticity in slices of adult mouse anterior piriform cortex maintained in




Abstract:
Tissue Nonspecific Alkaline Phosphatase (TNAP) is a key player of bone mineralization and TNAP gene (ALPL) mutations in human are responsible for hypophosphatasia (HPP), a rare heritable disease affecting the mineralization of bones and teeth. Moreover, TNAP is also expressed by brain cells and the severe forms of HPP are associated with neurological disorders, including epilepsy and brain morphological anomalies. However TNAP?s role in the nervous system remains poorly understood. In order to investigate its neuronal functions, we aimed to identify without any a priori the metabolites regulated by TNAP in the nervous tissue. For this purpose we used 1H- and 31P NMR to analyze the brain metabolome of Alpl (Akp2) mice null for TNAP function, a well-described model of infantile HPP. Among 39 metabolites identified in brain extracts of one week-old animals, 8 displayed significantly different concentration in Akp2?/? compared to Akp2+/+ and Akp2+/? mice: cystathionine, adenosine, GABA, methionine, histidine, 3-methylhistidine, N-acetylaspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG), with cystathionine and adenosine levels displaying the strongest alteration. These metabolites identify several biochemical processes that directly or indirectly involve TNAP function, in particular through the regulation of ecto-nucleotide levels and of pyridoxal phosphate-dependent enzymes. Some of these metabolites are involved in neurotransmission (GABA, adenosine), in myelin synthesis (NAA, NAAG), and in the methionine cycle and transsulfuration pathway (cystathionine, methionine). Their disturbances may contribute to the neurodevelopmental and neurological phenotype of HPP.




Abstract:
Neuronal activity is characterized by a diversity of oscillatory phenomena that are associated with multiple behavioral and cognitive processes, yet the functional consequences of these oscillations are not fully understood. Our aim was to determine whether and how these different oscillatory activities affect short-term synaptic plasticity (STP), using the olfactory system as a model. In response to odorant stimuli, the olfactory bulb displays a slow breathing rhythm as well as beta and gamma oscillations. Since the firing of olfactory bulb projecting neurons is phase-locked with beta and gamma oscillations, structures downstream from the olfactory bulb should be driven preferentially at these frequencies. We examined STP exhibited by olfactory bulb inputs in slices of adult mouse piriform cortex maintained in vitro in an in vivo-like ACSF (calcium concentration: 1.1 mM). We replaced the presynaptic neuronal firing rate by repeated electrical stimulation (frequency between 3.125 and 100 Hz) applied to the lateral olfactory tract. Our results revealed a considerable enhancement of postsynaptic response amplitude for stimulation frequencies in the beta and gamma range. A phenomenological model of STP fitted to the data suggests that the experimental results can be explained by the interplay between three mechanisms: a short-term facilitation mechanism (time constant ?160 msec), and two short-term depression mechanisms (recovery time constants <20 msec and ?140 msec). Increasing calcium concentration (2.2 mM) resulted in an increase in the time constant of facilitation and in a strengthening of the slowest depression mechanism. As a result, response enhancement was reduced and its peak shifted toward the low beta and alpha ranges while depression became predominant in the gamma band. Using environmental conditions corresponding to those that prevail in vivo, our study shows that STP in the lateral olfactory tract to layer Ia synapse allows amplification of olfactory bulb inputs at beta and gamma frequencies.