Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia.

Schizophrenia has a complex and heterogeneous molecular and clinical picture. Over the years of research on this disease, many factors have been suggested to contribute to its pathogenesis. Recently, the inflammatory processes have gained particular interest in the context of schizophrenia due to the increasing evidence from epidemiological, clinical and experimental studies. Within the immunological component, special attention has been brought to chemokines and their receptors. Among them, CX3C chemokine receptor 1 (CX3CR1), which belongs to the family of seven-transmembrane G protein-coupled receptors, and its cognate ligand (CX3CL1) constitute a unique system in the central nervous system. In the view of regulation of the brain homeostasis through immune response, as well as control of microglia reactivity, the CX3CL1-CX3CR1 system may represent an attractive target for further research and schizophrenia treatment. In the review, we described the general characteristics of the CX3CL1-CX3CR1 axis and the involvement of this signaling pathway in the physiological processes whose disruptions are reported to participate in mechanisms underlying schizophrenia. Furthermore, based on the available clinical and experimental data, we presented a guide to understanding the implication of the CX3CL1-CX3CR1 dysfunctions in the course of schizophrenia.

Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia.

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1ß, Tnf-α, Il-6, Arg1, Igf-1, Tgf-ß and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the "two-hit" hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the "second hit" in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.

The Emerging Role of the Double-Edged Impact of Arachidonic Acid- Derived Eicosanoids in the Neuroinflammatory Background of Depression.

Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling mediators that are engaged in both physiological and pathological processes in the brain. Recently, their implication in the prolonged inflammatory response has become a focus of particular interest because, in contrast to acute inflammation, chronic inflammatory processes within the central nervous system (CNS) are crucial for the development of brain pathologies including depression. The synthesis of eicosanoids is catalysed primarily by cyclooxygenases (COX), which are involved in the production of pro-inflammatory AA metabolites, including prostaglandins and thromboxanes. Moreover, eicosanoid synthesis is catalysed by lipoxygenases (LOXs), which generate both leukotrienes and anti-inflammatory derivatives such as lipoxins. Thus, AA metabolites have double- edged pro-inflammatory and anti-inflammatory, pro-resolving properties, and an imbalance between these metabolites has been proposed as a contributor or even the basis for chronic neuroinflammatory effects. This review focuses on important evidence regarding eicosanoid-related pathways (with special emphasis on prostaglandins and lipoxins) that has added a new layer of complexity to the idea of targeting the double-edged AA-derivative pathways for therapeutic benefits in depression. We also sought to explore future research directions that can support a pro-resolving response to control the balance between eicosanoids and thus to reduce the chronic neuroinflammation that underlies at least a portion of depressive disorders.

The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours.

BACKGROUND: The bidirectional communication between neurons and microglia is fundamental for the homeostasis and biological function of the central nervous system. Maternal immune activation (MIA) is considered to be one of the factors affecting these interactions. Accordingly, MIA has been suggested to be involved in several neuropsychiatric diseases, including schizophrenia. The crucial regulatory systems for neuron-microglia crosstalk are the CX3CL1-CX3CR1 and CD200-CD200R axes. METHODS: We aimed to clarify the impact of MIA on CX3CL1-CX3CR1 and CD200-CD200R signalling pathways in the brains of male Wistar rats in early and adult life by employing two neurodevelopmental models of schizophrenia based on the prenatal challenge with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly I:C). We also examined the effect of MIA on the expression of microglial markers and the profile of cytokines released in the brains of young offspring, as well as the behaviour of adult animals. Moreover, we visualized the localization of ligand-receptor systems in the hippocampal regions (CA1, CA3 and DG) and the frontal cortex of young rats exposed to MIA. The differences between groups were analysed using Student's t test. RESULTS: We observed that MIA altered developmental trajectories in neuron-microglia communication in the brains of young offspring, as evidenced by the disruption of CX3CL1-CX3CR1 and/or CD200-CD200R axes. Our data demonstrated the presence of abnormalities after LPS-induced MIA in levels of Cd40, Il-1ß, Tnf-α, Arg1, Tgf-ß and Il-10, as well as IBA1, IL-1ß and IL-4, while after Poly I:C-generated MIA in levels of Cd40, iNos, Il-6, Tgf-ß, Il-10, and IBA1, IL-1ß, TNF-α, IL-6, TGF-ß and IL-4 early in the life of male animals. In adult male rats that experienced prenatal exposure to MIA, we observed behavioural changes resembling a schizophrenia-like phenotype. CONCLUSIONS: Our study provides evidence that altered CX3CL1-CX3CR1 and/or CD200-CD200R pathways, emerging after prenatal immune challenge with LPS and Poly I:C, might be involved in the aetiology of schizophrenia.

Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200-CD200R and CX3CL1-CX3CR1 Systems.

Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron-microglia crosstalk, particularly CX3CL1-CX3CR1 and CD200-CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the "two-hit" hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1-CX3CR1 and CD200-CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the "second hit" wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity and anxiety-like behaviours. The most intriguing finding was observed in the prepulse inhibition (PPI) test, where the deficit in the sensorimotor gating was age-dependent and present only in part of the rats. We were able to distinguish the occurrence of two groups: responsive and non-responsive (without the deficit). Concurrently, based on the results of the biochemical studies, MIA disrupted mainly the CD200-CD200R system, while the changes of the CX3CL1-CX3CR1 axis were less evident in the frontal cortex of adult non-responsive offspring. MIA markedly affected the immune regulators of the CD200-CD200R pathway as we observed an increase in cortical IL-6 release in the responsive group and IL-4 in the non-responsive offspring. Importantly, the "second hit" generated disturbances at the behavioural and biochemical levels mostly in the non-responsive adult animals. Those offspring were characterized both by disturbed PPI and "priming" microglia. Altogether, the exposure to MIA altered the immunomodulatory mechanisms, including the CD200-CD200R axis, in the brain and sensitized animals to subsequent immunological challenges, leading to the manifestation of schizophrenia-like alterations.

The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology.

Chronic inflammatory processes within the central nervous system (CNS) are in part responsible for the development of neurodegenerative and psychiatric diseases. These processes are associated with, among other things, the increased and disturbed activation of microglia and the elevated production of proinflammatory factors. Recent studies indicated that the disruption of the process of resolution of inflammation (RoI) may be the cause of CNS disorders. It is shown that the RoI is regulated by endogenous molecules called specialized pro-resolving mediators (SPMs), which interact with specific membrane receptors. Some SPMs activate formyl peptide receptors (FPRs), which belong to the family of seven-transmembrane G protein-coupled receptors. These receptors take part not only in the proinflammatory response but also in the resolution of the inflammation process. Therefore, the activation of FPRs might have complex consequences. This review discusses the potential role of FPRs, and in particular the role of FPR2 subtype, in the brain under physiological and pathological conditions and their involvement in processes underlying neurodegenerative and psychiatric disorders as well as ischemia, the pathogenesis of which involves the dysfunction of inflammatory processes.

The Potential Role of Dysfunctions in Neuron-Microglia Communication in the Pathogenesis of Brain Disorders.

The bidirectional communication between neurons and microglia is fundamental for the proper functioning of the central nervous system (CNS). Chemokines and clusters of differentiation (CD) along with their receptors represent ligand-receptor signalling that is uniquely important for neuron - microglia communication. Among these molecules, CX3CL1 (fractalkine) and CD200 (OX-2 membrane glycoprotein) come to the fore because of their cell-type-specific localization. They are principally expressed by neurons when their receptors, CX3CR1 and CD200R, respectively, are predominantly present on the microglia, resulting in the specific axis which maintains the CNS homeostasis. Disruptions to this balance are suggested as contributors or even the basis for many neurological diseases. In this review, we discuss the roles of CX3CL1, CD200 and their receptors in both physiological and pathological processes within the CNS. We want to underline the critical involvement of these molecules in controlling neuron - microglia communication, noting that dysfunctions in their interactions constitute a key factor in severe neurological diseases, such as schizophrenia, depression and neurodegeneration-based conditions.