Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury.

Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1β to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with "A2" reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1β-induced model of NWMI, astrocytes also exhibit "A2" reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop "A2" reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection

Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury

Prenatal inflammatory insults accompany prematurity and provoke diffuse white matter injury (DWMI), which is associated with increased risk of neurodevelopmental pathologies, including autism spectrum disorders. DWMI results from maturation arrest of oligodendrocyte precursor cells (OPCs), a process that is poorly understood. Here, by using a validated mouse model of OPC maturation blockade, we provide the genome-wide ID card of the effects of neuroinflammation on OPCs that reveals the architecture of global cell fate issues underlining their maturation blockade. First, we find that, in OPCs, neuroinflammation takes advantage of a primed epigenomic landscape and induces abnormal overexpression of genes of the immune/inflammatory pathways: these genes strikingly exhibit accessible chromatin conformation in uninflamed OPCs, which correlates with their developmental, stage-dependent expression, along their normal maturation trajectory, as well as their abnormal upregulation upon neuroinflammation. Consistently, we observe the positioning on DNA of key transcription factors of the immune/inflammatory pathways (IRFs, NFkB), in both unstressed and inflamed OPCs. Second, we show that, in addition to the general perturbation of the myelination program, neuroinflammation counteracts the physiological downregulation of the cell cycle pathway in maturing OPCs. Neuroinflammation therefore perturbs cell identity in maturing OPCs, in a global manner. Moreover, based on our unraveling of the activity of genes of the immune/inflammatory pathways in prenatal uninflamed OPCs, the mere suppression of these proinflammatory mediators, as currently proposed in the field, may not be considered as a valid neurotherapeutic strategy

Transcriptionnal codes and expression of the GnRH receptor gene during development and in adult

Le récepteur hypophysaire de la GnRH (RGnRH) joue un rôle crucial dans le contrôle de la fonctionde reproduction. Dans le promoteur distal du Rgnrh, j’ai caractérisé un élément de réponsebifonctionnel répondant aux protéines LIM à homéodomaine ISL1/LHX3 et à GATA2. D’autre part,deux motifs TAAT situés dans la région plus proximale confèrent à ce gène la capacité de répondreaux facteurs Paired-like PROP1 et OTX2. Tous ces facteurs, exprimés précocement au cours del’ontogenèse hypophysaire, pourraient participer à l’émergence de l’expression du Rgnrh. Hors del’hypophyse, j’ai découvert que le Rgnrh est exprimé au cours du développement postnatal dansl’hippocampe de rat, où il module la plasticité synaptique. Par ailleurs, j’ai identifié deux nouveauxsites d’expression, la rétine et la glande pinéale. Ces résultats mettent en lumière l’importancefonctionnelle de ce récepteur et de son ligand et les rôles multiples qu’il ont acquis au cours del’évolution des Vertébrés.In the pituitary, the GnRH receptor (GnRHR) plays a crucial role in the neuroendocrine control ofreproductive function. Within the distal region of the Gnrhr promoter, I have characterized abifunctional response element modulated by the LIM homeodomain proteins ISL1/LHX3 and byGATA2. Besides, in the proximal region of the promoter, two TAAT motifs conferred response toPaired-like factors PROP1 and OTX2. All these factors are expressed during pituitary ontogenesis andcould participate in the onset and regulation of Gnrhr expression. Outside of the pituitary, I havediscovered that the Gnrhr was expressed during postnatal development in the rat hippocampus, whereit modulated synaptic plasticity. Furthermore, I have identified two novel sites of Gnrhr expression, theretina and the pineal gland. Altogether, these data highlight the functional importance of this receptorand its ligand as well as the multiple roles they have acquired during vertebrate evolution

Codes transcriptionnels et expression du gène du récepteur de la GnRH au cours du développement et chez l’adulte

In the pituitary, the GnRH receptor (GnRHR) plays a crucial role in the neuroendocrine control ofreproductive function. Within the distal region of the Gnrhr promoter, I have characterized abifunctional response element modulated by the LIM homeodomain proteins ISL1/LHX3 and byGATA2. Besides, in the proximal region of the promoter, two TAAT motifs conferred response toPaired-like factors PROP1 and OTX2. All these factors are expressed during pituitary ontogenesis andcould participate in the onset and regulation of Gnrhr expression. Outside of the pituitary, I havediscovered that the Gnrhr was expressed during postnatal development in the rat hippocampus, whereit modulated synaptic plasticity. Furthermore, I have identified two novel sites of Gnrhr expression, theretina and the pineal gland. Altogether, these data highlight the functional importance of this receptorand its ligand as well as the multiple roles they have acquired during vertebrate evolution.Le récepteur hypophysaire de la GnRH (RGnRH) joue un rôle crucial dans le contrôle de la fonctionde reproduction. Dans le promoteur distal du Rgnrh, j’ai caractérisé un élément de réponsebifonctionnel répondant aux protéines LIM à homéodomaine ISL1/LHX3 et à GATA2. D’autre part,deux motifs TAAT situés dans la région plus proximale confèrent à ce gène la capacité de répondreaux facteurs Paired-like PROP1 et OTX2. Tous ces facteurs, exprimés précocement au cours del’ontogenèse hypophysaire, pourraient participer à l’émergence de l’expression du Rgnrh. Hors del’hypophyse, j’ai découvert que le Rgnrh est exprimé au cours du développement postnatal dansl’hippocampe de rat, où il module la plasticité synaptique. Par ailleurs, j’ai identifié deux nouveauxsites d’expression, la rétine et la glande pinéale. Ces résultats mettent en lumière l’importancefonctionnelle de ce récepteur et de son ligand et les rôles multiples qu’il ont acquis au cours del’évolution des Vertébrés

Codes transcriptionnels et expression du gène du récepteur de la GnRH au cours du développement et chez l'adulte

Le récepteur hypophysaire de la GnRH (RGnRH) joue un rôle crucial dans le contrôle de la fonctionde reproduction. Dans le promoteur distal du Rgnrh, j ai caractérisé un élément de réponsebifonctionnel répondant aux protéines LIM à homéodomaine ISL1/LHX3 et à GATA2. D autre part,deux motifs TAAT situés dans la région plus proximale confèrent à ce gène la capacité de répondreaux facteurs Paired-like PROP1 et OTX2. Tous ces facteurs, exprimés précocement au cours del ontogenèse hypophysaire, pourraient participer à l émergence de l expression du Rgnrh. Hors del hypophyse, j ai découvert que le Rgnrh est exprimé au cours du développement postnatal dansl hippocampe de rat, où il module la plasticité synaptique. Par ailleurs, j ai identifié deux nouveauxsites d expression, la rétine et la glande pinéale. Ces résultats mettent en lumière l importancefonctionnelle de ce récepteur et de son ligand et les rôles multiples qu il ont acquis au cours del évolution des Vertébrés.In the pituitary, the GnRH receptor (GnRHR) plays a crucial role in the neuroendocrine control ofreproductive function. Within the distal region of the Gnrhr promoter, I have characterized abifunctional response element modulated by the LIM homeodomain proteins ISL1/LHX3 and byGATA2. Besides, in the proximal region of the promoter, two TAAT motifs conferred response toPaired-like factors PROP1 and OTX2. All these factors are expressed during pituitary ontogenesis andcould participate in the onset and regulation of Gnrhr expression. Outside of the pituitary, I havediscovered that the Gnrhr was expressed during postnatal development in the rat hippocampus, whereit modulated synaptic plasticity. Furthermore, I have identified two novel sites of Gnrhr expression, theretina and the pineal gland. Altogether, these data highlight the functional importance of this receptorand its ligand as well as the multiple roles they have acquired during vertebrate evolution.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Alcohol exposure promotes DNA methyltransferase DNMT3A upregulation through reactive oxygen species-dependent mechanisms

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Failure of thyroid hormone treatment to prevent inflammation-induced white matter injury in the immature brain

Preterm birth is very strongly associated with maternal/foetal inflammation and leads to permanent neurological deficits. These deficits correlate with the severity of white matter injury, including maturational arrest of oligodendrocytes and hypomyelination. Preterm birth and exposure to inflammation causes hypothyroxinemia. As such, supplementation with thyroxine (T4) seems a good candidate therapy for reducing white matter damage in preterm infants as oligodendrocyte maturation and myelination is regulated by thyroid hormones. We report on a model of preterm inflammation-induced white matter damage, in which induction of systemic inflammation by exposure from P1 to P5 to interleukin-1β (IL-1β) causes oligodendrocyte maturational arrest and hypomyelination. This model identified transient hypothyroidism and wide-ranging dysfunction in thyroid hormone signalling pathways. To test whether a clinically relevant dose of T4 could reduce inflammation-induced white matter damage we concurrently treated mice exposed to IL-1β from P1 to P5 with T4 (20 μg/kg/day). At P10, we isolated O4-positive pre-oligodendrocytes and gene expression analysis revealed that T4 treatment did not recover the IL-1β-induced blockade of oligodendrocyte maturation. Moreover, at P10 and P30 immunohistochemistry for markers of oligodendrocyte lineage (NG2, PDGFRα and APC) and myelin (MBP) similarly indicated that T4 treatment did not recover IL-1β-induced deficits in the white matter. In summary, in this model of preterm inflammation-induced white matter injury, a clinical dose of T4 had no therapeutic efficacy. We suggest that additional pre-clinical trials with T4 covering the breadth and scope of causes and outcomes of perinatal brain injury are required before we can correctly evaluate clinical trials data and understand the potential for thyroid hormone as a widely implementable clinical therapy

Glial response to 17β-estradiol in neonatal rats with excitotoxic brain injury

White-matter injury is the most common cause of the adverse neurodevelopmental outcomes observed in preterm infants. Only few options exist to prevent perinatal brain injury associated to preterm delivery. 17β-estradiol (E2) is the predominant estrogen in circulation and has been shown to be neuroprotective in vitro and in vivo. However, while E2 has been found to modulate inflammation in adult models of brain damage, how estrogens influence glial cells response in the developing brain needs further investigations. Using a model of ibotenate-induced brain injury, we have refined the effects of E2 in the developing brain. E2 provides significant neuroprotection both in the cortical plate and the white matter in neonatal rats subjected to excitotoxic insult mimicking white matter and cortical damages frequently observed in very preterm infants. E2 promotes significant changes in microglial phenotypes balance in response to brain injury and the acceleration of oligodendrocyte maturation. Maturational effects of E2 on myelination process were observed both in vivo and in vitro. Altogether, these data demonstrate that response of glial cells to E2 could be responsible for its neuroprotective properties in neonatal excitotoxic brain injury

Brain damage of the preterm infant:new insights into the role of inflammation

Epidemiological studies have shown a strong association between perinatal infection/inflammation and brain damage in preterm infants and/or neurological handicap in survivors. Experimental studies have shown a causal effect of infection/inflammation on perinatal brain damage. Infection including inflammatory factors can disrupt programmes of brain development and, in particular, induce death and/or blockade of oligodendrocyte maturation, leading to myelin defects. Alternatively, in the so-called multiple-hit hypothesis, infection/inflammation can act as predisposing factors, making the brain more susceptible to a second stress (sensitization process), such as hypoxic–ischaemic or excitotoxic insults. Epidemiological data also suggest that perinatal exposure to inflammatory factors could predispose to long-term diseases including psychiatric disorders.</jats:p