Estrogen receptor transrepresses brain inflammation.

Estrogen receptors (ERs) have long been implicated in the etiology of multiple sclerosis, but no clear molecular mechanisms have linked ERs to the disease's pathology. Now Saijo et al. (2011) provide evidence that ERß activates a transrepression pathway that suppresses inflammation and inhibits progression of pathology in a mouse model of multiple sclerosis.

Melatonin and vitamin D, two sides of the same coin, better to land on its edge to improve multiple sclerosis.

Previous studies revealed a latitudinal gradient of multiple sclerosis (MS) prevalence, increasing by moving from the equator to the poles. The duration and quality of an individual's exposure to sunlight vary with latitude. Skin exposure to sunlight activates vitamin D synthesis, while light absence, as perceived by the eyes, activates melatonin synthesis in the pineal gland. Vitamin D or melatonin deficiency/insufficiency or overdose can occur at any latitude due to specific lifestyles and diets. Moving away from the equator, especially beyond 37°, decreases vitamin D while raising melatonin. Furthermore, melatonin synthesis increases in cold habitats like northern countries. Since melatonin's beneficial role was shown in MS, it is expected that northern countries whose individuals have higher endogenous melatonin should show a lower MS prevalence; however, these are ranked with the highest scores. In addition, countries like the United States and Canada have uncontrolled over-the-counter usage. In high latitudes, vitamin D deficiency and a higher MS prevalence persist even though vitamin D is typically compensated for by supplementation and not sunlight. Recently, we found that prolonged darkness increased MS melatonin levels, mimicking the long-term increase in northern countries. This caused a reduction in cortisol and increased infiltration, inflammation, and demyelination, which were all rescued by constant light therapy. In this review, we explain melatonin and vitamin D's possible roles in MS prevalence. The possible causes in northern countries are then discussed. Finally, we suggest strategies to treat MS by manipulating vitamin D and melatonin, preferably with sunlight or darkness, not supplements.

Targeting Systemic Innate Immune Cells as a Therapeutic Avenue for Alzheimer Disease.

Alzheimer disease (AD) is the first progressive neurodegenerative disease worldwide, and the disease is characterized by an accumulation of amyloid in the brain and neurovasculature that triggers cognitive decline and neuroinflammation. The innate immune system has a preponderant role in AD. The last decade, scientists focused their efforts on therapies aiming to modulate innate immunity. The latter is of great interest, since they participate to the inflammation and phagocytose the amyloid in the brain and blood vessels. We and others have developed pharmacological approaches to stimulate these cells using various ligands. These include toll-like receptor 4, macrophage colony stimulating factor, and more recently nucleotide-binding oligomerization domain-containing 2 receptors. This review will discuss the great potential to take advantage of the innate immune system to fight naturally against amyloid ß accumulation and prevent its detrimental consequence on brain functions and its vascular system. SIGNIFICANCE STATEMENT: The focus on amyloid ß removal from the perivascular space rather than targeting CNS plaque formation and clearance represents a new direction with a great potential. Small molecules able to act at the level of peripheral immunity would constitute a novel approach for tackling aberrant central nervous system biology, one of which we believe would have the potential of generating a lot of interest.

The Synergistic Potential of Combining PD-1/PD-L1 Immune Checkpoint Inhibitors with NOD2 Agonists in Alzheimer's Disease Treatment.

Our research over the past decade has compellingly demonstrated the potential of Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) receptor agonists in Alzheimer's disease (AD) treatment. These agonists facilitate the conversation of pro-inflammatory monocytes into patrolling monocytes, leading to the efficient clearance of amyloid-ß (Aß) in the AD-affected cerebrovascular system. This approach surpasses the efficacy of targeting Aß formation, marking a significant shift in therapeutic strategies. Simultaneously, inhibitors of PD-1/PD-L1 immune check point or glycogen synthase kinase 3 beta (GSK3ß), which modulates PD-1, have emerged as potent AD treatment modalities. PD-1 inhibitor exhibits a profound potential in monocytes' recruitment to the AD-afflicted brain. Recent evidence suggests that an integrated approach, combining the modulation of NOD2 and PD-1, could yield superior outcomes. This innovative combinatorial therapeutic approach leverages the potential of MDP to act as a catalyst for the conversion of inflammatory monocytes into patrolling monocytes, with the subsequent recruitment of these patrolling monocytes into the brain being stimulated by the PD-1 inhibitor. These therapeutic interventions are currently under preclinical investigation by pharmaceutical entities, underscoring the promise they hold. This research advocates for the modulation, rather than suppression, of the innate immune system as a promising pharmacological strategy in AD.

Context-dependent transcriptional regulation of microglial proliferation.

Microglia proliferate during brain development and brain lesions, but how this is coordinated at the transcriptional level is not well understood. Here, we investigated fundamental aspects of the transcriptional process associated with proliferation of mouse microglia during postnatal development and in adults in a model of induced microglial depletion-repopulation. While each proliferative subset displayed globally a distinct signature of gene expression, they also co-expressed a subgroup of 1370 genes at higher levels than quiescent microglia. Expression of these may be coordinated by one of two mechanisms of regulation with distinct properties. A first mechanism augments expression of genes already expressed in quiescent microglia and is subject to regulation by Klf/Sp, Nfy, and Ets transcription factors. Alternatively, a second mechanism enables de novo transcription of cell cycle genes and requires additional regulatory input from Lin54 and E2f transcription factors. Of note, transcriptional upregulation of E2f1 and E2f2 family members may represent a critical regulatory checkpoint to enable microglia to achieve efficient cell cycling. Furthermore, analysis of the activity profile of the repertoire of promoter-distal genomic regulatory elements suggests a relatively restricted role for these elements in coordinating cell cycle gene expression in microglia. Overall, proliferating microglia integrates regulation of cell cycle gene expression with their broader, context-dependent, transcriptional landscape.

Inhibition of PLK2 activity affects APP and tau pathology and improves synaptic content in a sex-dependent manner in a 3xTg mouse model of Alzheimer's disease.

Converging lines of evidence suggest that abnormal accumulation of the kinase Polo-like kinase 2 (PLK2) might play a role in the pathogenesis of Alzheimer's disease (AD), possibly through its role in regulating the amyloid ß (Aß) cascade. In the present study, we investigated the effect of inhibiting PLK2 kinase activity in in vitro and in vivo models of AD neuropathology. First, we confirmed that PLK2 overexpression modulated APP and Tau protein levels and phosphorylation in cell culture, in a kinase activity dependent manner. Furthermore, a transient treatment of triple transgenic mouse model of AD (3xTg-AD) with a potent and specific PLK2 pharmacological inhibitor (PLK2i #37) reduced some neuropathological aspects in a sex-dependent manner. In 3xTg-AD males, treatment with PLK2i #37 led to lower Tau burden, higher synaptic protein content, and prevented learning and memory deficits. In contrast, treated females showed an exacerbation of Tau pathology, associated with a reduction in amyloid plaque accumulation. Overall, our findings suggest that PLK2 inhibition alters key components of AD neuropathology in a sex-dependent manner and might display a therapeutic potential for the treatment for AD and related dementia.

Reduced melatonin levels may facilitate glioblastoma initiation in the subventricular zone.

There is increasing evidence that glioblastoma, a highly aggressive brain tumour, originates from a neural stem cell (NSC) located in the subventricular zone (SVZ) of the lateral cerebral ventricle. Using the most advanced in vivo imaging techniques, Gengatharan and colleagues recently identified a day/night difference in the adult SVZ-NSC division. They reported that the circadian melatonin rhythm and its receptor control the day/night difference in NSC division with high mitotic activity during the day and low activity at night. Expression of melatonin and its receptor diminishes during ageing, which eliminates the regulatory effect of melatonin on NSC mitosis. Moreover, the circadian melatonin rhythm is dampened by light-at-night with the potential of altering the circadian mitotic cycle of NSC in the SVZ. Also, men with a lower melatonin amplitude than women exhibit a 60% higher rate of glioblastoma incidence. Given that ageing contributes significantly to glioblastoma initiation and progression, we suggest that the decline in circadian melatonin synthesis and release as well as its receptors in the SVZ, which also diminish with an ageing act in concert with other factors to facilitate glioblastoma initiation and growth.

Early monocyte modulation by the non-erythropoietic peptide ARA 290 decelerates AD-like pathology progression.

Alzheimer's disease (AD) pathology is characterized by amyloid-ß (Aß) deposition and tau hyper-phosphorylation, accompanied by a progressive cognitive decline. Monocytes have been recently shown to play a major role in modulating Aß pathology, and thereby have been pointed as potential therapeutic targets. However, the main challenge remains in identifying clinically relevant interventions that could modulate monocyte immune functions in absence of undesired off-target effects. Erythropoietin (EPO), a key regulator of erythrocyte production, has been shown to possess immunomodulatory potential and to provide beneficial effects in preclinical models of AD. However, the transition to use recombinant human EPO in clinical trials was hindered by unwanted erythropoietic effects that could lead to thrombosis. Here, we used a recently identified non-erythropoietic analogue of EPO, ARA 290, to evaluate its therapeutic potential in AD therapy. We first evaluated the effects of early systemic ARA 290 administration on AD-like pathology in an early-onset model, represented by young APP/PS1 mice. Our findings indicate that ARA 290 early treatment decelerated Aß pathology progression in APP/PS1 mice while improving cognitive functions. ARA 290 potently increased the levels of total monocytes by specifically stimulating the generation of Ly6CLow patrolling subset, which are implicated in clearing Aß from the cerebral vasculature, and subsequently reducing overall Aß burden in the brain. Moreover, ARA 290 increased the levels of monocyte progenitors in the bone marrow. Using chimeric APP/PS1 mice in which Ly6CLow patrolling subset are selectively depleted, ARA 290 was inefficient in attenuating Aß pathology and ameliorating cognitive functions in young animals. Interestingly, ARA 290 effects were compromised when delivered in a late-onset model, represented by aged APP1/PS1. In aged APP/PS1 mice in which AD-like pathology is at advanced stages, ARA 290 failed to reverse Aß pathology and to increase the levels of circulating monocytes. Our study suggests that ARA 290 early systemic treatment could prevent AD-like progression via modulation of monocyte functions by specifically increasing the ratio of patrolling monocytes.

Targeting innate immunity to protect and cure Alzheimer's disease: opportunities and pitfalls.

Innate immunity has been the focus of many new directions to understand the mechanisms involved in the aetiology of brain diseases, especially Alzheimer's disease (AD). AD is a multifactorial disorder, with the innate immune response and neuroinflammation at the forefront of the pathology. Thus, microglial cells along with peripheral circulating monocytes and more generally the innate immune response have been the target of several pre-clinical and clinical studies. More than a decade ago, inhibiting innate immune cells was considered to be the critical angle for preventing and treating brain diseases. After the failing of numerous clinical trials and the discovery that it may actually be the opposite in various pre-clinical models, the field has changed considerably. Here, we present both sides of the story with a particular emphasis on the beneficial properties of innate immune cells and how they can be targeted to have neuroprotective properties.

An Early Microglial Response Is Needed To Efficiently Control Herpes Simplex Virus Encephalitis.

The role of a signaling pathway through macrophage colony-stimulating factor (MCSF) and its receptor, macrophage colony-stimulating factor 1 receptor (CSF1R), during experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE) was studied by two different approaches. First, we evaluated the effect of stimulation of the MCSF/CSF1R axis before infection. Exogenous MCSF (40 µg/kg of body weight intraperitoneally [i.p.]) was administered once daily to BALB/c mice on days 4 and 2 before intranasal infection with 2,500 PFU of HSV-1. MCSF treatment significantly increased mouse survival compared to saline (50% versus 10%; P = 0.0169). On day 6 postinfection (p.i.), brain viral titers were significantly decreased, whereas beta interferon (IFN-ß) was significantly increased in mice treated with MCSF compared to mice treated with saline. The number of CD68+ (a phagocytosis marker) microglial cells was significantly increased in MCSF-treated mice compared to the saline-treated group. Secondly, we conditionally depleted CSF1R on microglial cells of CSF1R-loxP-CX3CR1-cre/ERT2 mice (in a C57BL/6 background) through induction with tamoxifen. The mice were then infected intranasally with 600,000 PFU of HSV-1. The survival rate of mice depleted of CSF1R (knockout [KO] mice) was significantly lower than that of wild-type (WT) mice (0% versus 67%). Brain viral titers and cytokine/chemokine levels were significantly higher in KO than in WT animals on day 6 p.i. Furthermore, increased infiltration of monocytes into the brains of WT mice was seen on day 6 p.i., but not in KO mice. Our results suggest that microglial cells are essential to control HSE at early stages of the disease and that the MCSF/CSF1R axis could be a therapeutic target to regulate their response to infection.IMPORTANCE Microglia appear to be one of the principal regulators of neuroinflammation in the central nervous system (CNS). An increasing number of studies have demonstrated that the activation of microglia could result in either beneficial or detrimental effects in different CNS disorders. Hence, the role of microglia during herpes simplex virus encephalitis (HSE) has not been fully characterized. Using experimental mouse models, we showed that an early activation of the MCSF/CSF1R axis improved the outcome of the disease, possibly by inducing a proliferation of microglia. In contrast, depletion of microglia before HSV-1 infection worsened the prognosis of HSE. Thus, an early microglial response followed by sustained infiltration of monocytes and T cells into the brain seem to be key components for a better clinical outcome. These data suggest that microglia could be a potential target for immunomodulatory strategies combined with antiviral therapy to better control the outcome of this devastating disease.

Inflammatory Monocytes and Neutrophils Regulate Streptococcus suis-Induced Systemic Inflammation and Disease but Are Not Critical for the Development of Central Nervous System Disease in a Mouse Model of Infection.

Streptococcus suis is an important porcine bacterial pathogen and zoonotic agent responsible for sudden death, septic shock, and meningitis. These pathologies are a consequence of elevated bacterial replication leading to exacerbated and uncontrolled inflammation, a hallmark of the S. suis systemic and central nervous system (CNS) infections. Monocytes and neutrophils are immune cells involved in various functions, including proinflammatory mediator production. Moreover, monocytes are composed of two main subsets: shorter-lived inflammatory monocytes and longer-lived patrolling monocytes. However, regardless of their presence in blood and the fact that S. suis-induced meningitis is characterized by infiltration of monocytes and neutrophils into the CNS, their role during the S. suis systemic and CNS diseases remains unknown. Consequently, we hypothesized that monocytes and neutrophils participate in S. suis infection via bacterial clearance and inflammation. Results demonstrated that inflammatory monocytes and neutrophils regulate S. suis-induced systemic disease via their role in inflammation required for bacterial burden control. In the CNS, inflammatory monocytes contributed to exacerbation of S. suis-induced local inflammation, while neutrophils participated in bacterial burden control. However, development of clinical CNS disease was independent of both cell types, indicating that resident immune cells are mostly responsible for S. suis-induced CNS inflammation and clinical disease and that inflammatory monocyte and neutrophil infiltration is a consequence of the induced inflammation. In contrast, the implication of patrolling monocytes was minimal throughout the S. suis infection. Consequently, this study demonstrates that while inflammatory monocytes and neutrophils modulate S. suis-induced systemic inflammation and disease, they are not critical for CNS disease development.

Muramyl dipeptide-mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer's disease.

BACKGROUND: Muramyl dipeptide (MDP) is a component derived from minimal peptidoglycan motif from bacteria, and it is a ligand for the NOD2 receptor. Peripheral administration of MDP converts Ly6Chigh into Ly6Clow monocytes. Previously, we have shown that Ly6Clow monocytes play crucial roles in the pathology of a mouse model of Alzheimer's disease (AD). However, medications with mild immunomodulatory effects that solely target specific monocyte subsets, without triggering microglial activation, are rare. METHODS: Three months old APPswe/PS1 transgenic male mice and age-matched C57BL/6 J mice were used for high frequency (2 times/week) over 6 months and low frequency (once a week) over 3 months of intraperitoneally MDP (10 mg/kg) administrations. Flow cytometry analysis of monocyte subsets in blood, and behavioral and postmortem analyses were performed. RESULTS: Memory tests showed mild to a strong improvement in memory function, increased expression levels of postsynaptic density protein 95 (PSD95), and low-density lipoprotein receptor-related protein 1 (LRP1), which are involved in synaptic plasticity and amyloid-beta (Aß) elimination, respectively. In addition, we found monocyte chemoattractant protein-1(MCP-1) levels significantly increased, whereas intercellular adhesion molecule-1(ICAM-1) significantly decreased, and microglial marker (Iba1) did not change in the treatment group compared to the control. In parallel, we discovered elevated cyclooxygenase-2 (COX2) expression levels in the treated group, which might be a positive factor for synaptic activity. CONCLUSIONS: Our results demonstrate that MDP is beneficial in both the early phase and, to some extent, later phases of the pathology in the mouse model of AD. These data open the way for potential MDP-based medications for AD.

Whole-exome sequencing identifies homozygous mutation in TTI2 in a child with primary microcephaly: a case report.

BACKGROUND: Primary microcephaly is defined as reduced occipital-frontal circumference noticeable before 36 weeks of gestation. Large amount of insults might lead to microcephaly including infections, hypoxia and genetic mutations. More than 16 genes are described in autosomal recessive primary microcephaly. However, the cause of microcephaly remains unclear in many cases after extensive investigations and genetic screening. CASE PRESENTATION: Here, we described the case of a boy with primary microcephaly who presented to a neurology clinic with short stature, global development delay, dyskinetic movement, strabismus and dysmorphic features. We performed microcephaly investigations and genetic panels. Then, we performed whole-exome sequencing to identify any genetic cause. Microcephaly investigations and genetic panels were negative, but we found a new D317V homozygous mutation in TELOE-2 interacting protein 2 (TTI2) gene by whole-exome sequencing. TTI2 is implicated in DNA damage response and mutation in that gene was previously described in mental retardation, autosomal recessive 39. CONCLUSIONS: We described the first French Canadian case with primary microcephaly and global developmental delay secondary to a new D317V homozygous mutation in TTI2 gene. Our report also highlights the importance of TTI2 protein in brain development.

Ultrastructural evidence of microglial heterogeneity in Alzheimer's disease amyloid pathology.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by the deposition of extracellular fibrillar amyloid ß (fΑß) and the intracellular accumulation of neurofibrillary tangles. As AD progresses, Aß drives a robust and prolonged inflammatory response via its recognition by microglia, the brain's immune cells. Microglial reactivity to fAß plaques may impair their normal surveillance duties, facilitating synaptic loss and neuronal death, as well as cognitive decline in AD. METHODS: In the current study, we performed correlative light, transmission, and scanning electron microscopy to provide insights into microglial structural and functional heterogeneity. We analyzed microglial cell bodies and processes in areas containing fAß plaques and neuronal dystrophy, dystrophy only, or appearing healthy, among the hippocampus CA1 of 14-month-old APPSwe-PS1Δe9 mice versus wild-type littermates. RESULTS: Our quantitative analysis revealed that microglial cell bodies in the AD model mice were larger and displayed ultrastructural signs of cellular stress, especially nearby plaques. Microglial cell bodies and processes were overall less phagocytic in AD model mice. However, they contained increased fibrillar materials and non-empty inclusions proximal to plaques. Microglial cell bodies and processes in AD model mice also displayed reduced association with extracellular space pockets that contained debris. In addition, microglial processes in healthy subregions of AD model mice encircled synaptic elements more often compared with plaque-associated processes. These observations in mice were qualitatively replicated in post-mortem hippocampal samples from two patients with AD (Braak stage 5). CONCLUSION: Together, our findings identify at the ultrastructural level distinct microglial transformations common to mouse and human in association with amyloid pathology.

Chondroitin sulfate proteoglycans as novel drivers of leucocyte infiltration in multiple sclerosis.

Multiple sclerosis presents with profound changes in the network of molecules involved in maintaining central nervous system architecture, the extracellular matrix. The extracellular matrix components, particularly the chondroitin sulfate proteoglycans, have functions beyond structural support including their potential interaction with, and regulation of, inflammatory molecules. To investigate the roles of chondroitin sulfate proteoglycans in multiple sclerosis, we used the experimental autoimmune encephalomyelitis model in a time course study. We found that the 4-sulfated glycosaminoglycan side chains of chondroitin sulfate proteoglycans, and the core protein of a particular family member, versican V1, were upregulated in the spinal cord of mice at peak clinical severity, correspondent with areas of inflammation. Versican V1 expression in the spinal cord rose progressively over the course of experimental autoimmune encephalomyelitis. A particular structure in the spinal cord and cerebellum that presented with intense upregulation of chondroitin sulfate proteoglycans is the leucocyte-containing perivascular cuff, an important portal of entry of immune cells into the central nervous system parenchyma. In these inflammatory perivascular cuffs, versican V1 and the glycosaminoglycan side chains of chondroitin sulfate proteoglycans were observed by immunohistochemistry within and in proximity to lymphocytes and macrophages as they migrated across the basement membrane into the central nervous system. Expression of versican V1 transcript was also documented in infiltrating CD45+ leucocytes and F4/80+ macrophages by in situ hybridization. To test the hypothesis that the chondroitin sulfate proteoglycans regulate leucocyte mobility, we used macrophages in tissue culture studies. Chondroitin sulfate proteoglycans significantly upregulated pro-inflammatory cytokines and chemokines in macrophages. Strikingly, and more potently than the toll-like receptor-4 ligand lipopolysaccharide, chondroitin sulfate proteoglycans increased the levels of several members of the matrix metalloproteinase family, which are implicated in the capacity of leucocytes to cross barriers. In support, the migratory capacity of macrophages in vitro in a Boyden chamber transwell assay was enhanced by chondroitin sulfate proteoglycans. Finally, using brain specimens from four subjects with multiple sclerosis with active lesions, we found chondroitin sulfate proteoglycans to be associated with leucocytes in inflammatory perivascular cuffs in all four patients. We conclude that the accumulation of chondroitin sulfate proteoglycans in the perivascular cuff in multiple sclerosis and experimental autoimmune encephalomyelitis boosts the activity and migration of leucocytes across the glia limitans into the central nervous system parenchyma. Thus, chondroitin sulfate proteoglycans represent a new class of molecules to overcome in order to reduce the inflammatory cascades and clinical severity of multiple sclerosis.

Role of the chemokine receptors CCR2 and CX3CR1 in an experimental model of thrombotic stroke.

Stroke is the second cause of mortality worldwide and occurs following the interruption of cerebral blood circulation by cerebral vessel burst or subsequent to a local thrombus formation. Ischemic lesion triggers an important inflammatory response, characterized by massive infiltration of leukocytes, activation of glial cells and neurovascular reorganization. Chemokines and their receptors, such as CCR2 and CX3CR1, play an important role in leukocyte recruitment in the damaged area. Mice genetically depleted for the two receptors CCR2 and CX3CR1 underwent focal cerebral ischemia, based on the topical application of ferric chloride to truncate the distal middle cerebral artery. The infarct, limited only to the cortical area, remained stable in WT mice, while it is reduced overtime in the transgenic mice. Moreover, we did not observe any significant changes in the level of the inflammatory response in the infarcted areas while immune cell infiltration and neurovascularization are modulated according to genotype. Our results show that the genetic deletion of both CCR2 and CX3CR1 receptors has neuroprotective effects in response to a cerebral permanent ischemia. This study underlines a key role of CCR2- and CX3CR1-expressing immune cells in the neuropathology associated with ischemic injuries.

A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-1.

Interleukin-1 (IL-1) has multiple functions in both the periphery and the central nervous system (CNS) and is regulated at many levels. We identified an isoform of the IL-1 receptor (IL-1R) accessory protein (termed AcPb) that is expressed exclusively in the CNS. AcPb interacted with IL-1 and the IL-1R but was unable to mediate canonical IL-1 responses. AcPb expression, however, modulated neuronal gene expression in response to IL-1 treatment in vitro. Animals lacking AcPb demonstrated an intact peripheral IL-1 response and developed experimental autoimmune encephalomyelitis (EAE) similarly to wild-type mice. AcPb-deficient mice were instead more vulnerable to local inflammatory challenge in the CNS and suffered enhanced neuronal degeneration as compared to AcP-deficient or wild-type mice. These findings implicate AcPb as an additional component of the highly regulated IL-1 system and suggest that it may play a role in modulating CNS responses to IL-1 and the interplay between inflammation and neuronal survival.

Bone marrow-derived macrophages and the CNS: An update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders.

The central nervous system (CNS) is a very unique system with multiple features that differentiate it from systemic tissues. One of the most captivating aspects of its distinctive nature is the presence of the blood brain barrier (BBB), which seals it from the periphery. Therefore, to preserve tissue homeostasis, the CNS has to rely heavily on resident cells such as microglia. These pivotal cells of the mononuclear lineage have important and dichotomous roles according to various neurological disorders. However, certain insults can overwhelm microglia as well as compromising the integrity of the BBB, thus allowing the infiltration of bone marrow-derived macrophages (BMDMs). The use of myeloablation and bone marrow transplantation allowed the generation of chimeric mice to study resident microglia and infiltrated BMDM separately. This breakthrough completely revolutionized the way we captured these 2 types of mononuclear phagocytic cells. We now realize that microglia and BMDM exhibit distinct features and appear to perform different tasks. Since these cells are central in several pathologies, it is crucial to use chimeric mice to analyze their functions and mechanisms to possibly harness them for therapeutic purpose. This review will shed light on the advent of this methodology and how it allowed deciphering the ontology of microglia and its maintenance during adulthood. We will also compare the different strategies used to perform myeloablation. Finally, we will discuss the landmark studies that used chimeric mice to characterize the roles of microglia and BMDM in several neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

Immunosenescence of microglia and macrophages: impact on the ageing central nervous system.

Ageing of the central nervous system results in a loss of both grey and white matter, leading to cognitive decline. Additional injury to both the grey and white matter is documented in many neurological disorders with ageing, including Alzheimer's disease, traumatic brain and spinal cord injury, stroke, and multiple sclerosis. Accompanying neuronal and glial damage is an inflammatory response consisting of activated macrophages and microglia, innate immune cells demonstrated to be both beneficial and detrimental in neurological repair. This article will propose the following: (i) infiltrating macrophages age differently from central nervous system-intrinsic microglia; (ii) several mechanisms underlie the differential ageing process of these two distinct cell types; and (iii) therapeutic strategies that selectively target these diverse mechanisms may rejuvenate macrophages and microglia for repair in the ageing central nervous system. Most responses of macrophages are diminished with senescence, but activated microglia increase their expression of pro-inflammatory cytokines while diminishing chemotactic and phagocytic activities. The senescence of macrophages and microglia has a negative impact on several neurological diseases, and the mechanisms underlying their age-dependent phenotypic changes vary from extrinsic microenvironmental changes to intrinsic changes in genomic integrity. We discuss the negative effects of age on neurological diseases, examine the response of senescent macrophages and microglia in these conditions, and propose a theoretical framework of therapeutic strategies that target the different mechanisms contributing to the ageing phenotype in these two distinct cell types. Rejuvenation of ageing macrophage/microglia may preserve neurological integrity and promote regeneration in the ageing central nervous system.