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Infants born very preterm (below 28 weeks of gestation) are at high risk of developing neurodevelopmental disorders, such as intellectual deficiency, autism spectrum disorders, and attention deficit. Preterm birth often occurs in the context of perinatal systemic inflammation due to chorioamnionitis and postnatal sepsis. In addition, C-section is often performed for very preterm neonates to avoid hypoxia during a vaginal delivery. We have developed and characterized a mouse model based on intraperitoneal injections of IL-1β between postnatal days one and five to reproduce perinatal systemic inflammation. This model replicates several neuropathological, brain imaging, and behavioral deficits observed in preterm infants. We hypothesized that C-sections could synergize with systemic inflammation to induce more severe brain abnormalities. We observed that C-sections significantly exacerbated the deleterious effects of IL-1β on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced functional connectivity in the brain relative to vaginal delivery plus intraperitoneal saline. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation on brain maldevelopment and malfunction, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Human mesenchymal stem cells modulate the immune response and are good candidates for cell therapy in neuroinflammatory brain disorders affecting both adult and premature infants. Recent evidence indicates that through their secretome, mesenchymal stem cells direct microglia, brain-resident immune cells, toward pro-regenerative functions, but the mechanisms underlying microglial phenotypic transition are still under investigation. Using an in vitro coculture approach combined with transcriptomic analysis, we identified the extracellular matrix as the most relevant pathway altered by the human mesenchymal stem cell secretome in the response of microglia to inflammatory cytokines. We confirmed extracellular matrix remodeling in microglia exposed to the mesenchymal stem cell secretome via immunofluorescence analysis of the matrix component fibronectin and the extracellular crosslinking enzyme transglutaminase-2. Furthermore, an analysis of hallmark microglial functions revealed that changes in the extracellular matrix enhance ruffle formation by microglia and cell motility. These findings point to extracellular matrix changes, associated plasma membrane remodeling, and enhanced microglial migration as novel mechanisms by which mesenchymal stem cells contribute to the pro-regenerative microglial transition.

Microglia and border-associated macrophages play critical roles in both immunity and neurodevelopment. The disruption of microglial development trajectories by neonatal inflammation is an important issue in research on neurodevelopmental disorders (NDDs), as models have suggested a strong association between inflammation and cognitive deficits. Here, we explored by single-cell RNA sequencing and flow cytometry the impact of neonatal inflammation in a mouse NDD model on brain myeloid cell subsets. A specific subset of microglia expressing the complement receptor C5ar1 has been identified, in which inflammatory pathways are most strongly activated. Based on transcriptional similarity, this subset appears to originate from the most mature and "homeostatic" microglia at this stage of development and demonstrated hypersensitivity to inflammation. Besides that, Spp1-microglia supporting oligodendrocyte differentiation, primitive and proliferative microglia were reduced by inflammation. These findings suggest major changes in microglial subsets developmental trajectories and reactivity contributing to NDDs induced by neonatal inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Despite improved management of traumatic brain injury (TBI), it still leads to lifelong sequelae and disability, particularly in children. Chronic neuroinflammation (the so-called tertiary phase), in particular, microglia/macrophage and astrocyte reactivity, is among the main mechanisms suspected of playing a role in the generation of lesions associated with TBI. The role of acute neuroinflammation is now well understood, but its persistent effect and impact on the brain, particularly during development, are not. Here, we investigated the long-term effects of pediatric TBI on the brain in a mouse model., Methods: Pediatric TBI was induced in mice on postnatal day (P) 7 by weight-drop trauma. The time course of neuroinflammation and myelination was examined in the TBI mice. They were also assessed by magnetic resonance, functional ultrasound, and behavioral tests at P45., Results: TBI induced robust neuroinflammation, characterized by acute microglia/macrophage and astrocyte reactivity. The long-term consequences of pediatric TBI studied on P45 involved localized scarring astrogliosis, persistent microgliosis associated with a specific transcriptomic signature, and a long-lasting myelination defect consisting of the loss of myelinated axons, a decreased level of myelin binding protein, and severe thinning of the corpus callosum. These results were confirmed by reduced fractional anisotropy, measured by diffusion tensor imaging, and altered inter- and intra-hemispheric connectivity, measured by functional ultrasound imaging. In addition, adolescent mice with pediatric TBI showed persistent social interaction deficits and signs of anxiety and depressive behaviors., Conclusions: We show that pediatric TBI induces tertiary neuroinflammatory processes associated with white matter lesions and altered behavior. These results support our model as a model for preclinical studies for tertiary lesions following TBI., (Copyright © 2024. Published by Elsevier Inc.)

Preterm birth and its related complications have become more and more common as neonatal medicine advances. The concept of "developmental origins of health and disease" has raised awareness of adverse perinatal events in the development of diseases later in life. To explore this concept, we propose that encephalopathy of prematurity (EoP) as a potential pro-inflammatory early life event becomes a novel risk factor for metabolic diseases in children/adolescents and adulthood. Here, we review epidemiological evidence that links preterm birth to metabolic diseases and discuss possible synergic roles of preterm birth and neuroinflammation from EoP in the development of metabolic diseases. In addition, we explore theoretical underlying mechanisms regarding developmental programming of the energy control system and HPA axis., Competing Interests: There are no conflict of interest among all authors.", (© 2024 The Authors.)

Across the globe, approximately one in 10 babies are born preterm, that is, before 37 weeks of a typical 40 weeks of gestation. Up to 50% of preterm born infants develop brain injury, encephalopathy of prematurity (EoP), that substantially increases their risk for developing lifelong defects in motor skills and domains of learning, memory, emotional regulation, and cognition. We are still severely limited in our abilities to prevent or predict preterm birth. No longer just the "support cells," we now clearly understand that during development glia are key for building a healthy brain. Glial dysfunction is a hallmark of EoP, notably, microgliosis, astrogliosis, and oligodendrocyte injury. Our knowledge of glial biology during development is exponentially expanding but hasn't developed sufficiently for development of effective neuroregenerative therapies. This review summarizes the current state of knowledge for the roles of glia in infants with EoP and its animal models, and a description of known glial-cell interactions in the context of EoP, such as the roles for border-associated macrophages. The field of perinatal medicine is relatively small but has worked passionately to improve our understanding of the etiology of EoP coupled with detailed mechanistic studies of pre-clinical and human cohorts. A primary finding from this review is that expanding our collaborations with computational biologists, working together to understand the complexity of glial subtypes, glial maturation, and the impacts of EoP in the short and long term will be key to the design of therapies that improve outcomes., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)

Understanding the long-term functional implications of gut microbial communities during the perinatal period is a bourgeoning area of research. Numerous studies have revealed the existence of a "gut-brain axis" and the impact of an alteration of gut microbiota composition in brain diseases. Recent research has highlighted how gut microbiota could affect brain development and behavior. Many factors in early life such as the mode of delivery or preterm birth could lead to disturbance in the assembly and maturation of gut microbiota. Notably, global rates of cesarean sections (C-sections) have increased in recent decades and remain important when considering premature delivery. Both preterm birth and C-sections are associated with an increased risk of neurodevelopmental disorders such as autism spectrum disorders, with neuroinflammation a major risk factor. In this review, we explore links between preterm birth by C-sections, gut microbiota alteration, and neuroinflammation. We also highlight C-sections as a risk factor for developmental disorders due to alterations in the microbiome., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

G protein-coupled receptor 17 (GPR17) and the WNT pathway are critical players of oligodendrocyte (OL) differentiation acting as essential timers in developing brain to achieve fully-myelinating cells. However, whether and how these two systems are related to each other is still unknown. Of interest, both factors are dysregulated in developing and adult brain diseases, including white matter injury and cancer, making the understanding of their reciprocal interactions of potential importance for identifying new targets and strategies for myelin repair. Here, by a combined pharmacological and biotechnological approach, we examined regulatory mechanisms linking WNT signaling to GPR17 expression in OLs. We first analyzed the relative expression of mRNAs encoding for GPR17 and the T cell factor/Lymphoid enhancer-binding factor-1 (TCF/LEF) transcription factors of the canonical WNT/β-CATENIN pathway, in PDGFRα + and O4 + OLs during mouse post-natal development. In O4 + cells, Gpr17 mRNA level peaked at post-natal day 14 and then decreased concomitantly to the physiological uprise of WNT tone, as shown by increased Lef1 mRNA level. The link between WNT signaling and GPR17 expression was further reinforced in vitro in primary PDGFRα + cells and in Oli-neu cells. High WNT tone impaired OL differentiation and drastically reduced GPR17 mRNA and protein levels. In Oli-neu cells, WNT/β-CATENIN activation repressed Gpr17 promoter activity through both putative WNT response elements (WRE) and upregulation of the inhibitor of DNA-binding protein 2 (Id2). We conclude that the WNT pathway influences OL maturation by repressing GPR17, which could have implications in pathologies characterized by dysregulations of the OL lineage including multiple sclerosis and oligodendroglioma., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Approximately 15 million babies are born prematurely every year and many will face lifetime motor and/or cognitive deficits. Children born prematurely are at higher risk of developing perinatal brain lesions, especially white matter injuries (WMI). Evidence in humans and rodents demonstrates that systemic inflammation-induced neuroinflammation, including microglial and astrocyte reactivity, is the prominent processes of WMI associated with preterm birth. Thus, a new challenge in the field of perinatal brain injuries is to develop new neuroprotective strategies to target neuroinflammation to prevent WMI. Serotonin (5-HT) and its receptors play an important role in inflammation, and emerging evidence indicates that 5-HT may regulate brain inflammation by the modulation of microglial reactivity and astrocyte functions. The present study is based on a mouse model of WMI induced by intraperitoneal (i.p.) injections of IL-1β during the first 5 days of life. In this model, certain key lesions of preterm brain injuries can be summarized by (i) systemic inflammation, (ii) pro-inflammatory microglial and astrocyte activation, and (iii) inhibition of oligodendrocyte maturation, leading to hypomyelination. We demonstrate that Htr7 mRNA (coding for the HTR7/5-HT7 receptor) is significantly overexpressed in the anterior cortex of IL-1β-exposed animals, suggesting it as a potential therapeutic target. LP-211 is a specific high-affinity HTR7 agonist that crosses the blood-brain barrier (BBB). When co-injected with IL-1β, LP-211 treatment prevented glial reactivity, the down-regulation of myelin-associated proteins, and the apparition of anxiety-like phenotypes. Thus, HTR7 may represent an innovative therapeutic target to protect the developing brain from preterm brain injuries., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

In the central nervous system, lipids represent approximately 70% of myelin dry weight and play a key role in axon insulation and action potential conduction velocity. Lipids may thus represent sensitive markers of myelin status in physiological and pathological contexts. In this study, a comprehensive lipidomic analysis by ultra-high-performance liquid chromatography and high-resolution mass spectrometry was performed on myelin-enriched fractions prepared from mouse brains. Two developmental stages were compared: an early rapid myelination stage (postnatal day 15, P15), and a late basal myelination stage (P40). Besides an expected enrichment in characteristic myelin lipids, our study revealed a profound remodeling in phospholipid subclasses during myelination. It included a dramatic decrease in phosphatidylcholine (PC) content and an increase in phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) contents, concomitant to an increased proportion of monounsaturated fatty acids (MUFA) in these subclasses. Lipidomic results were supported by upregulated expression of genes involved in PE, PI, PS and MUFA synthesis in maturing O4+ oligodendrocytes. Highlighted lipid changes may represent key features of brain myelination that could be explored in the context of myelin pathologies., Competing Interests: Declaration of competing interest All authors have approved the final article., (Copyright © 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Preterm infants often show pathologies of the cerebellum, which are associated with impaired motor performance, lower IQ and poor language skills at school ages. Using a mouse model of inflammation-induced encephalopathy of prematurity driven by systemic administration of pro-inflammatory IL-1β, we sought to uncover causes of cerebellar damage. In this model, IL-1β is administered between postnatal day (P) 1 to day 5, a timing equivalent to the last trimester for brain development in humans. Structural MRI analysis revealed that systemic IL-1β treatment induced specific reductions in gray and white matter volumes of the mouse cerebellar lobules I and II (5% false discovery rate [FDR]) from P15 onwards. Preceding these MRI-detectable cerebellar volume changes, we observed damage to oligodendroglia, with reduced proliferation of OLIG2+ cells at P10 and reduced levels of the myelin proteins myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) at P10 and P15. Increased density of IBA1+ cerebellar microglia were observed both at P5 and P45, with evidence for increased microglial proliferation at P5 and P10. Comparison of the transcriptome of microglia isolated from P5 cerebellums and cerebrums revealed significant enrichment of pro-inflammatory markers in microglia from both regions, but cerebellar microglia displayed a unique type I interferon signaling dysregulation. Collectively, these data suggest that perinatal inflammation driven by systemic IL-1β leads to specific cerebellar volume deficits, which likely reflect oligodendrocyte pathology downstream of microglial activation. Further studies are now required to confirm the potential of protective strategies aimed at preventing sustained type I interferon signaling driven by cerebellar microglia as an important therapeutic target., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Microglia, as brain resident macrophages, are fundamental to several functions, including response to environmental stress and brain homeostasis. Microglia can adopt a large spectrum of activation phenotypes. Moreover, microglia that endorse pro-inflammatory phenotype is associated with both neurodevelopmental and neurodegenerative disorders. In vitro studies are widely used in research to evaluate potential therapeutic strategies in specific cell types. In this context studying microglial activation and neuroinflammation in vitro using primary microglial cultures is more relevant than microglial cell lines or stem-cell-derived microglia. However, the use of some primary cultures might suffer from a lack of reproducibility. This protocol proposes a reproducible and relevant method of magnetically isolating microglia from neonate pups. Microglial activation using several stimuli after 4 h and 24 h by mRNA expression quantification and a Cy3-bead phagocytic assay is demonstrated here. The current work is expected to provide an easily reproducible technique for isolating physiologically relevant microglia from juvenile developmental stages.

Preterm birth (PTB) represents 15 million births every year worldwide and is frequently associated with maternal/fetal infections and inflammation, inducing neuroinflammation. This neuroinflammation is mediated by microglial cells, which are brain-resident macrophages that release cytotoxic molecules that block oligodendrocyte differentiation, leading to hypomyelination. Some preterm survivors can face lifetime motor and/or cognitive disabilities linked to periventricular white matter injuries (PWMIs). There is currently no recommendation concerning the mode of delivery in the case of PTB and its impact on brain development. Many animal models of induced-PTB based on LPS injections exist, but with a low survival rate. There is a lack of information regarding clinically used pharmacological substances to induce PTB and their consequences on brain development. Mifepristone (RU-486) is a drug used clinically to induce preterm labor. This study aims to elaborate and characterize a new model of induced-PTB and PWMIs by the gestational injection of RU-486 and the perinatal injection of pups with IL-1beta. A RU-486 single subcutaneous (s.c.) injection at embryonic day (E)18.5 induced PTB at E19.5 in pregnant OF1 mice. All pups were born alive and were adopted directly after birth. IL-1beta was injected intraperitoneally from postnatal day (P)1 to P5. Animals exposed to both RU-486 and IL-1beta demonstrated microglial reactivity and subsequent PWMIs. In conclusion, the s.c. administration of RU-486 induced labor within 24 h with a high survival rate for pups. In the context of perinatal inflammation, RU-486 labor induction significantly decreases microglial reactivity in vivo but did not prevent subsequent PWMIs.

Inflammation appears as a cardinal mediator of the deleterious effect of early life stress exposure on neurodevelopment. More generally, immune activation during the perinatal period, and most importantly elevations of pro-inflammatory cytokines levels could contribute to psychopathology and neurological deficits later in life. Cytokines are also required for normal brain function in homeostatic conditions and play a role in neurodevelopmental processes. Despite these latter studies, whether pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF) impact neurodevelopmental trajectories and behavior during the immediate postnatal period remains to be elucidated. To address this issue, we have injected mouse pups daily with recombinant TNF from postnatal day (P)1 to P5. This yielded a robust increase in peripheral and central TNF at P5, and also an increase of additional pro-inflammatory cytokines. Compared to control pups injected with saline, mice injected with TNF acquired the righting and the acoustic startle reflexes more rapidly and exhibited increased locomotor activity 2 weeks after birth. Our results extend previous work restricted to adult behaviors and support the notion that cytokines, and notably TNF, modulate early neurodevelopmental trajectories., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Paraschivescu, Barbosa, Van Steenwinckel, Gressens, Glaichenhaus and Davidovic.)

Objectives: In the premature newborn, perinatal inflammation mediated by microglia contributes significantly to neurodevelopmental injuries including white matter injury (WMI). Brain inflammation alters development through neuroinflammatory processes mediated by activation of homeostatic microglia toward a pro-inflammatory and neurotoxic phenotype. Investigating immune regulators of microglial activation is crucial to find effective strategies to prevent and treat WMI., Methods: Ex vivo microglial cultures and a mouse model of WMI induced by perinatal inflammation (interleukin-1-beta [IL-1β] and postnatal days 1-5) were used to uncover and elucidate the role of microRNA-146b-5p in microglial activation and WMI., Results: A specific reduction in vivo in microglia of Dicer, a protein required for microRNAs maturation, reduces pro-inflammatory activation of microglia and prevents hypomyelination in our model of WMI. Microglial miRNome analysis in the WMI model identified miRNA-146b-5p as a candidate modulator of microglial activation. Ex vivo microglial cell culture treated with the pro-inflammatory stimulus lipopolysaccharide (LPS) led to overexpression of immunomodulatory miRNA-146b-5p but its drastic reduction in the microglial extracellular vesicles (EVs). To increase miRNA-146b-5p expression, we used a 3DNA nanocarrier to deliver synthetic miRNA-146b-5p specifically to microglia. Enhancing microglial miRNA-146b-5p overexpression significantly decreased LPS-induced activation, downregulated IRAK1, and restored miRNA-146b-5p levels in EVs. In our WMI model, 3DNA miRNA-146b-5p treatment significantly prevented microglial activation, hypomyelination, and cognitive defect induced by perinatal inflammation., Interpretations: These findings support that miRNA-146b-5p is a major regulator of microglia phenotype and could be targeted to reduce the incidence and the severity of perinatal brain injuries and their long-term consequences. ANN NEUROL 2022;91:48-65., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Microglial activation during critical phases of brain development can result in short- and long-term consequences for neurological and psychiatric health. Several studies in humans and rodents have shown that microglial activation, leading to a transition from the homeostatic state toward a proinflammatory phenotype, has adverse effects on the developing brain and neurodevelopmental disorders. Targeting proinflammatory microglia may be an effective strategy for protecting the brain and attenuating neurodevelopmental disorders induced by inflammation. In this review we focus on the role of inflammation and the activation of immature microglia (pre-microglia) soon after birth in prematurity-associated neurodevelopmental disorders, and the specific features of pre-microglia during development. We also highlight the relevance of immunomodulatory strategies for regulating activated microglia in a rodent model of perinatal brain injury. An original neuroprotective approach involving a nanoparticle-based therapy and targeting microglia, with the aim of improving myelination and protecting the developing brain, is also addressed., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Acquired perinatal brain injuries are a set of conditions that remains a key challenge for neonatologists and that have significant social, emotional and financial implications for our communities. In our perspective article, we will introduce perinatal brain injury focusing specifically on the events leading to brain damage in preterm born infants and outcomes for these infants. Then we will summarize and discuss the preclinical and clinical studies testing the efficacy of stem cells as neuroprotectants in the last ten years in perinatal brain injury. There are no therapies to treat brain damage in preterm born infants and a primary finding from this review is that there is a scarcity of stem cell trials focused on overcoming brain injuries in these infants. Overall, across all forms of perinatal brain injury there is a remarkable heterogeneity in previous and on-going preclinical and clinical studies in terms of the stem cell type, animal models/patient selection, route and time of administration. Despite the quality of many of the studies this variation makes it difficult to reach a valid consensus for future developments. However, it is clear that stem cells (and stem cell derived exosomes) can reduce perinatal brain injury and our field needs to work collectively to refine an effective protocol for each type of injury. The use of standardized stem cell products and testing these products across multiple models of injury will provide a stronger framework for clinical trials development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation and numerous reports show that OLs express several receptors for immune related molecules, which enable them to sense inflammation and to react. However, the role of OL immune response in WMI is unclear. Here, we focus our study on toll-like receptor-3 (TLR3) that is activated by double-strand RNA (dsRNA) and promotes neuroinflammation. Despite its importance, its expression and role in OLs remain unclear. We used an in vivo mouse model, which mimics inflammation-mediated WMI of preterm born infants consisting of intraperitoneal injection of IL-1β from P1 to P5. In the IL-1β-treated animals, we observed the upregulation of Tlr3, IL-1β, IFN-β, Ccl2, and Cxcl10 in both PDGFRα+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFRα+ OL precursor cells (OPCs), suggesting a different sensitivity to neuroinflammation. These observations were confirmed in OL primary cultures: cells treated with TLR3 agonist Poly(I:C) during differentiation showed a stronger upregulation of Ccl2 and Cxcl10 compared to cells treated during proliferation and led to decreased expression of myelin genes. Finally, OLs were able to modulate microglia phenotype and function depending on their maturation state as assessed by qPCR using validated markers for immunomodulatory, proinflammatory, and anti-inflammatory phenotypes and by phagocytosis and morphological analysis. These results show that during inflammation the response of OLs can play an autonomous role in blocking their own differentiation: in addition, the immune activation of OLs may play an important role in shaping the response of microglia during inflammation.

Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these.

Meta-analyses have revealed associations between the incidence of maternal infections during pregnancy, premature birth, smaller brain volumes, and subsequent cognitive, motor and behavioral deficits as these children mature. Inflammation during pregnancy in rodents produces cognitive and behavioral deficits in the offspring that are similar to those reported in human studies. These deficits are accompanied by decreased neurogenesis and proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. As systemically administering interleukin-1 β (IL-1β) to neonatal mice recapitulates many of the brain abnormalities seen in premature babies including developmental delays, the goal of this study was to determine whether IL-1-mediated neuroinflammation would affect hippocampal growth during development to produce cognitive and behavioral abnormalities. For these studies, 10 ​ng/g IL-1β was administered twice daily to Swiss Webster mice during the first 5 days of life, which increased hippocampal levels of IL-1α and acutely reduced the proliferation of Tbr2 + neural progenitors in the DG. In vitro , both IL-1α and IL-1β produced G1/S cell cycle arrest that resulted in reduced progenitor cell proliferation within the transit amplifying progenitor cell cohort. By contrast, IL-1β treatment increased neural stem cell frequency. Upon terminating IL-1β treatment, the progenitor cell pool regained its proliferative capacity. An earlier study that used this in vivo model of perinatal inflammation showed that mice that received IL-1β as neonates displayed memory deficits which suggested abnormal hippocampal function. To evaluate whether other cognitive and behavioral traits associated with hippocampal function would also be altered, mice were tested in tasks designed to assess exploratory and anxiety behavior as well as working and spatial memory. Interestingly, mice that received IL-1β as neonates showed signs of anxiety in several behavioral assays during adolescence that were also evident in adulthood. Additionally, these mice did not display working memory deficits in adulthood, but they did display deficits in long-term spatial memory. Altogether, these data support the view that perinatal inflammation negatively affects the developing hippocampus by producing behavioral deficits that persist into adulthood. These data provide a new perspective into the origin of the cognitive and behavioral impairments observed in prematurely-born sick infants., Competing Interests: The authors have no conflicts of interest to report., (© 2020 The Authors.)

Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Major depressive disorder is a complex multifactorial condition with a so far poorly characterized underlying pathophysiology. Consequently, the available treatments are far from satisfactory as it is estimated that up to 30% of patients are resistant to conventional treatment. Recent comprehensive evidence has been accumulated which suggests that inflammation may be implied in the etiology of this disease. Here we investigated ketamine as an innovative treatment strategy due to its immune-modulating capacities. In a murine model of LPS-induced depressive-like behavior we demonstrated that a single dose of ketamine restores the LPS-induced depressive-like alterations. These behavioral effects are associated with i/ a reversal of anxiety and reduced self-care, ii/ a decrease in parenchymal cytokine production, iii/ a modulation of the microglial reactivity and iv/ a decrease in microglial quinolinic acid production that is correlated with plasmatic peripheral production. In a translational approach, we show that kynurenic acid to quinolinic acid ratio is a predictor of ketamine response in treatment-resistant depressed patients and that the reduction in quinolinic acid after a ketamine infusion is a predictor of the reduction in MADRS score. Our results suggest that microglia is a key therapeutic target and that quinolinic acid is a biomarker of ketamine response in major depressive disorder., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The present study examined the involvement of zinc (Zn)-transporters (ZnT3) in cadmium (Cd)-induced alterations of Zn homeostasis in rat hippocampal neurons. We treated primary rat hippocampal neurons for 24 or 48 hr with various concentrations of CdCl 2 (0, 0.5, 5, 10, 25, or 50 μM) and/or ZnCl 2 (0, 10, 30, 50, 70, or 90 μM), using normal neuronal medium as control. By The CellTiter 96 ® Aqueous One Solution Cell Proliferation Assay (MTS; Promega, Madison, WI) assay and immunohistochemistry for cell death markers, 10 and 25 μM of Cd were found to be noncytotoxic doses, and both 30 and 90 μM of Zn as the best concentrations for cell proliferation. We tested these selected doses. Cd, at concentrations of 10 or 25 μM (and depending on the absence or presence of Zn), decreased the percentage of surviving cells. Cd-induced neuronal death was either apoptotic or necrotic depending on dose, as indicated by 7-AAD and/or annexin V labeling. At the molecular level, Cd exposure induced a decrease in hippocampal brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) and Erk1/2 signaling, a significant downregulation of the expression of learning- and memory-related receptors and synaptic proteins such as the NMDAR NR2A subunit and PSD-95, as well as the expression of the synapse-specific vesicular Zn transporter ZnT3 in cultured hippocampal neurons. Zn supplementation, especially at the 30 μM concentration, led to partial or total protection against Cd neurotoxicity both with respect to the number of apoptotic cells and the expression of several genes. Interestingly, after knockdown of ZnT3 by small interfering RNA transfection, we did not find the restoration of the expression of this gene following Zn supplementation at 30 μM concentration. These data indicate the involvement of ZnT3 in the mechanism of Cd-induced hippocampal neurotoxicity., (© 2019 Wiley Periodicals, Inc.)

Genetic anomalies have a role in autism spectrum disorders (ASD). Each genetic factor is responsible for a small fraction of cases. Environment factors, like preterm delivery, have an important role in ASD. Preterm infants have a 10-fold higher risk of developing ASD. Preterm birth is often associated with maternal/fetal inflammation, leading to a fetal/neonatal inflammatory syndrome. There are demonstrated experimental links between fetal inflammation and the later development of behavioral symptoms consistent with ASD. Preterm infants have deficits in connectivity. Most ASD genes encode synaptic proteins, suggesting that ASD are connectivity pathologies. Microglia are essential for normal synaptogenesis. Microglia are diverted from homeostatic functions towards inflammatory phenotypes during perinatal inflammation, impairing synaptogenesis. Preterm infants with ASD have a different phenotype from term born peers. Our original hypothesis is that exposure to inflammation in preterm infants, combined with at risk genetic background, deregulates brain development leading to ASD.

Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination. WMI is induced by mimicking the effects of maternal-fetal infection-inflammation and setting up neuroinflammation. We induce this process at the time in the mouse when brain development is equivalent to the human third trimester; postnatal day (P)1 through to P5 with i.p. interleukin-1β (IL-1β) injections. We initiated GSK247246 treatment (i.p at 7 mg/kg or 20 mg/kg) after neuroinflammation was well established (on P6) and it was administered twice daily through to P10. Outcomes were assessed at P10 and P30 with gene and protein analysis. A low dose of GSK247246 (7 mg/kg) lead to a recovery in protein expression of markers of myelin (density of Myelin Basic Protein, MBP & Proteolipid Proteins, PLP) and a reduction in macro- and microgliosis (density of ionising adaptor protein, IBA1 & glial fibrillary acid protein, GFAP). Our results confirm the neurotherapeutic efficacy of targeting the H3R for WMI seen in a cuprizone model of multiple sclerosis and a recently reported clinical trial in relapsing-remitting multiple sclerosis patients. Further work is needed to develop a slow release strategy for this agent and test its efficacy in large animal models of preterm infant WMI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning ("Causal Reasoning Analytical Framework for Target discovery"-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy.

Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7 -deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10 , Nkx2.2 , and Gpr17 However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Traumatic brain injury (TBI) results in white matter injury (WMI) that is associated with neurological deficits. Neuroinflammation originating from microglial activation may participate in WMI and associated disorders. To date, there is little information on the time courses of these events after mild TBI. Therefore we investigated (i) neuroinflammation, (ii) WMI and (iii) behavioral disorders between 6 hours and 3 months after mild TBI. For that purpose, we used experimental mild TBI in mice induced by a controlled cortical impact. (i) For neuroinflammation, IL-1b protein as well as microglial phenotypes, by gene expression for 12 microglial activation markers on isolated CD11b+ cells from brains, were studied after TBI. IL-1b protein was increased at 6 hours and 1 day. TBI induced a mixed population of microglial phenotypes with both pro-inflammatory, anti-inflammatory and immunomodulatory markers from 6 hours to 3 days post-injury. At 7 days, microglial activation was completely resolved. (ii) Three myelin proteins were assessed after TBI on ipsi- and contralateral corpus callosum, as this structure is enriched in white matter. TBI led to an increase in 2',3'-cyclic-nucleotide 3'-phosphodiesterase, a marker of immature and mature oligodendrocyte, at 2 days post-injury; a bilateral demyelination, evaluated by myelin basic protein, from 7 days to 3 months post-injury; and an increase in myelin oligodendrocyte glycoprotein at 6 hours and 3 days post-injury. Transmission electron microscopy study revealed various myelin sheath abnormalities within the corpus callosum at 3 months post-TBI. (iii) TBI led to sensorimotor deficits at 3 days post-TBI, and late cognitive flexibility disorder evidenced by the reversal learning task of the Barnes maze 3 months after injury. These data give an overall invaluable overview of time course of neuroinflammation that could be involved in demyelination and late cognitive disorder over a time-scale of 3 months in a model of mild TBI. This model could help to validate a pharmacological strategy to prevent post-traumatic WMI and behavioral disorders following mild TBI.

Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.Inflammation mediated by microglia plays a key role in brain injury associated with preterm birth, but little is known about the microglial response in preterm infants. Here, the authors integrate molecular and imaging data from animal models and preterm infants, and find that microglial expression of DLG4 plays a role.

Perinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term-born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection., (© The Authors. Journal compilation © 2015 Mac Keith Press.)

Neuropathic pain resulting from peripheral nerve injury involves many persistent neuroinflammatory processes including inflammatory chemokines that control leukocyte trafficking and activate resident cells. Several studies have shown that CCL2 chemokine, a potent attractant of monocytes, and its cognate receptor, CCR2, play a critical role in regulating nociceptive processes during neuropathic pain. However, the role of CCL2 in peripheral leukocyte infiltration-associated neuropathic pain remains poorly understood. In particular, the contribution of individual CCL2-expressing cell populations (i.e. stromal and leukocytes) to immune cell recruitment into the injured nerve has not been established. Here, in preclinical model of peripheral neuropathic pain (i.e. chronic constriction injury of the sciatic nerve), we have demonstrated that, CCL2 content was increased specifically in nerve fibers. This upregulation of CCL2 correlated with local monocyte/macrophage infiltration and pain processing. Furthermore, sciatic intraneural microinjection of CCL2 in naïve animals triggered long-lasting pain behavior associated with local monocyte/macrophage recruitment. Using a specific CCR2 antagonist and mice with a CCL2 genetic deletion, we have also established that the CCL2/CCR2 axis drives monocyte/macrophage infiltration and pain hypersensitivity in the CCI model. Finally, specific deletion of CCL2 in stromal or immune cells respectively using irradiated bone marrow-chimeric CCI mice demonstrated that stromal cell-derived CCL2 (in contrast to CCL2 immune cell-derived) tightly controls monocyte/macrophage recruitment into the lesion and plays a major role in the development of neuropathic pain. These findings demonstrate that in chronic pain states, CCL2 expressed by sciatic nerve cells predominantly drove local neuro-immune interactions and pain-related behavior through CCR2 signaling., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Chorioamnionitis, an inflammatory gestational disorder, commonly precedes preterm delivery. Preterm infants may be at particular risk for inflammation-related morbidity related to infection, although the pathogenic mechanisms are unclear. We hypothesized that maternal inflammation modulates immune programming to drive postnatal inflammatory processes., Methods: We used a novel combined murine model to treat late gestation dams with low-dose lipopolysaccharide (LPS) and to secondarily challenge exposed neonates or weanlings with Sendai virus (SeV) lung infection. Multiple organs were analyzed to characterize age-specific postnatal immune and inflammatory responses., Results: Maternal LPS treatment enhanced innate immune populations in the lungs, livers, and/or spleens of exposed neonates or weanlings. Secondary lung SeV infection variably affected neutrophil, macrophage, and dendritic cell proportions in multiple organs of exposed pups. Neonatal lung infection induced brain interleukin (IL)-4 expression, although this response was muted in LPS-exposed pups. Adaptive immune cells, including lung, lymph node, and thymic lymphocytes and lung CD4 cells expressing FoxP3, interferon (IFN)-γ, or IL-17, were variably prominent in LPS-exposed pups., Conclusion: Maternal inflammation modifies postnatal immunity and augments systemic inflammatory responses to viral lung infection in an age-specific manner. We speculate that inflammatory modulation of the developing immune system contributes to chronic morbidity and mortality in preterm infants.

Functional interactions between the chemokine receptor CXCR4 and opioid receptors have been reported in the brain, leading to a decreased morphine analgesic activity. However the cellular mechanisms responsible for this loss of opioid analgesia are largely unknown. Here we examined whether Src family-kinases (SFK)-linked mechanisms induced by CXCR4 contributed to the loss of acute morphine analgesia and could represent a new physiological anti-opioid signaling pathway. In this way, we showed by immunohistochemistry and western blot that CXCL12 rapidly activated SFK phosphorylation in vitro in primary cultured lumbar rat dorsal root ganglia (DRG) but also in vivo in the DRG and the spinal cord. We showed that SFK activation occurred in a sub population of sensory neurons, in spinal microglia but also in spinal nerve terminals expressing mu-(MOR) and delta-opioid (DOR) receptor. In addition we described that CXCR4 is detected in MOR- and DOR-immunoreactive neurons in the DRG and spinal cord. In vivo, we demonstrated that an intrathecal administration of CXCL12 (1μg) significantly attenuated the subcutaneous morphine (4mg/kg) analgesia. Conversely, pretreatment with a potent CXCR4 antagonist (5μg) significantly enhanced morphine analgesia. Similar effects were obtained after an intrathecal injection of a specific SFK inhibitor, PP2 (10μg). Furthermore, PP2 abrogated CXCL12-induced decrease in morphine analgesia by suppressing SFK activation in the spinal cord. In conclusion, our data highlight that CXCL12-induced loss of acute morphine analgesia is linked to Src family kinases activation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemokines - chemotactic cytokines - are small secreted proteins that attract and activate immune and non-immune cells in vitro and in vivo. It has been suggested that chemokines and their receptors play a role in the central nervous system (CNS), in addition to their well established role in the immune system. We focus here on three chemokines-CXCL12 (C-X-C motif ligand 12), CCL2 (C-C motif ligand 2), and CX3CL1 (C-X-3C motif ligand 1) - and their principal receptors - CXCR4 (C-X-C motif receptor 4), CCR2 (C-C motif receptor 2) and CX3CR1 (C-X-3C motif receptor 1), respectively. We first introduce the classification of chemokines and their G-protein coupled receptors and the main signaling pathways triggered by receptor activation. We then discuss the cellular distribution of CXCL12/CXCR4, CCL2/CCR2 and CX3CL1/CX3CR1 in adult brain and the neurotransmission and neuromodulation effects controlled by these chemokines in the adult CNS. Changes in the expression of CXCL12, CCL2 and CX3CL1 and their respective receptors are also increasingly being implicated in the pathogenesis of CNS disorders, such as Alzheimer's disease, Parkinson's disease, HIV-associated encephalopathy, stroke and multiple sclerosis, and are therefore plausible targets for future pharmacological intervention. The final section thus discusses the role of these chemokines in these pathophysiological states. In conclusion, the role of these chemokines in cellular communication may make it possible: (i) to identify new pathways of neuron-neuron, glia-glia or neuron-glia communications relevant to both normal brain function and neuroinflammatory and neurodegenerative diseases; (ii) to develop new therapeutic approaches for currently untreatable brain diseases., (Published by Elsevier Ltd.)

Recent observations suggest that besides their role in the immune system, chemokines have important functions in the brain. There is a great line of evidence to suggest that chemokines are a unique class of neurotransmitters/neuromodulators, which regulate many biological aspects as diverse as neurodevelopment, neuroinflammation and synaptic transmission. In physiopathological conditions, many chemokines are synthesized in activated astrocytes and microglial cells, suggesting their involvement in brain defense mechanisms. However, when evoking chemokine functions in the nervous system, it is important to make a distinction between resting conditions and various pathological states including inflammatory diseases, autoimmune or neurodegenerative disorders in which chemokine functions have been extensively studied. We illustrate here the emergent concept of the neuromodulatory/neurotransmitter activities of neurochemokines and their potential role as a regulatory alarm system and as a group of messenger molecules for the crosstalk between neurons and cells from their surrounding microenvironment. In this deliberately challenging review, we provide novel hypotheses on the role of these subtle messenger molecules in brain functions leading to the evidence that previous dogmas concerning chemokines should be reconsidered., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)