Central Nervous System Resident Cells Research Articles

The microbiota restrains neurodegenerative microglia in a model of amyotrophic lateral sclerosis

BackgroundThe gut microbiota can affect neurologic disease by shaping microglia, the primary immune cell in the central nervous system (CNS). While antibiotics improve models of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and the C9orf72 model of amyotrophic lateral sclerosis (ALS), antibiotics worsen disease progression the in SOD1G93A model of ALS. In ALS, microglia transition from a homeostatic to a neurodegenerative (MGnD) phenotype and contribute to disease pathogenesis, but whether this switch can be affected by the microbiota has not been investigated.ResultsIn this short report, we found that a low-dose antibiotic treatment worsened motor function and decreased survival in the SOD1 mice, which is consistent with studies using high-dose antibiotics. We also found that co-housing SOD1 mice with wildtype mice had no effect on disease progression. We investigated changes in the microbiome and found that antibiotics reduced Akkermansia and butyrate-producing bacteria, which may be beneficial in ALS, and cohousing had little effect on the microbiome. To investigate changes in CNS resident immune cells, we sorted spinal cord microglia and found that antibiotics downregulated homeostatic genes and increased neurodegenerative disease genes in SOD1 mice. Furthermore, antibiotic-induced changes in microglia preceded changes in motor function, suggesting that this may be contributing to disease progression.ConclusionsOur findings suggest that the microbiota play a protective role in the SOD1 model of ALS by restraining MGnD microglia, which is opposite to other neurologic disease models, and sheds new light on the importance of disease-specific interactions between microbiota and microglia.79u2nPu_HHhuYkV_eZR1DPVideo abstract

TH Cells and Cytokines in Encephalitogenic Disorders.

The invasion of immune cells into the central nervous system (CNS) is a hallmark of the process we call neuroinflammation. Diseases such as encephalitides or multiple sclerosis (MS) are characterised by the dramatic influx of T lymphocytes and monocytes. The communication between inflammatory infiltrates and CNS resident cells is primarily mediated through cytokines. Over the years, numerous cytokine networks have been assessed to better understand the development of immunopathology in neuroinflammation. In MS for instance, many studies have shown that CD4+ T cells infiltrate the CNS and subsequently lead to immunopathology. Inflammatory CD4+ T cells, such as TH1, TH17, GM-CSF-producing helper T cells are big players in chronic neuroinflammation. Conversely, encephalitogenic or meningeal regulatory T cells (TREGs) and TH2 cells have been shown to drive a decrease in inflammatory functions in microglial cells and thus promote a neuroprotective microenvironment. Recent studies report overlapping as well as differential roles of these cells in tissue inflammation. Taken together, this suggests a more complex relationship between effector T cell subsets in neuroinflammation than has hitherto been established. In this overview, we review the interplay between helper T cell subsets infiltrating the CNS and how they actively contribute to neuroinflammation and degeneration. Importantly, in this context, we will especially focus on the current knowledge regarding the contribution of various helper cell subsets to neuroinflammation by referring to their helper T cell profile in the context of their target cell.

Molecular Mechanisms of Immunosenescene and Inflammaging: Relevance to the Immunopathogenesis and Treatment of Multiple Sclerosis.

Aging is characterized, amongst other features, by a complex process of cellular senescence involving both innate and adaptive immunity, called immunosenescence and associated to inflammaging, a low-grade chronic inflammation. Both processes fuel each other and partially explain increasing incidence of cancers, infections, age-related autoimmunity, and vascular disease as well as a reduced response to vaccination. Multiple sclerosis (MS) is a lifelong disease, for which considerable progress in disease-modifying therapies (DMTs) and management has improved long-term survival. However, disability progression, increasing with age and disease duration, remains. Neurologists are now involved in caring for elderly MS patients, with increasing comorbidities. Aging of the immune system therefore has relevant implications for MS pathogenesis, response to DMTs and the risks mediated by these treatments. We propose to review current evidence regarding markers and molecular mechanisms of immunosenescence and their relevance to understanding MS pathogenesis. We will focus on age-related changes in the innate and adaptive immune system in MS and other auto-immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The consequences of these immune changes on MS pathology, in interaction with the intrinsic aging process of central nervous system resident cells will be discussed. Finally, the impact of immunosenescence on disease evolution and on the safety and efficacy of current DMTs will be presented.

Expression of antimicrobial host defence peptides in the central nervous system during health and disease.

Antimicrobial host defence peptides (HDP) are critical for the first line of defence against bacterial, viral, and fungal pathogens. Over the past decade we have become more aware that, in addition to their antimicrobial roles, they also possess the potent immunomodulatory capacity. This includes chemoattracting immune cells, activating dendritic cells and macrophages, and altering T-cell differentiation. Most examinations of their immunomodulatory roles have focused on tissues in which they are very abundant, such as the intestine and the inflamed skin. However, HDP have now been detected in the brain and the spinal cord during a number of conditions. We propose that their presence in the central nervous system (CNS) during homeostasis, infection, and neurodegenerative disease has the potential to contribute to immunosurveillance, alter host responses and skew developing immunity. Here, we review the evidence for HDP expression and function in the CNS in health and disease. We describe how a wide range of HDP are expressed in the CNS of humans, rodents, birds, and fish, suggesting a conserved role in protecting the brain from pathogens, with evidence of production by resident CNS cells. We highlight differences in methodology used and how this may have resulted in the immunomodulatory roles of HDP being overlooked. Finally, we discuss what HDP expression may mean for CNS immune responses.

Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update.

Injuries to the nervous system can result in a debilitating neuropathic pain state that is often resistant to treatment with available analgesics, which are commonly associated with several side-effects. Growing pre-clinical and clinical evidence over the last two decades indicates that immune cell-mediated mechanisms both in the periphery and in the Central Nervous System (CNS) play significant roles in the establishment and maintenance of neuropathic pain. Specifically, following peripheral nerve injury, microglia, which are CNS resident immune cells, respond to the activity of the first pain synapse in the dorsal horn of spinal cord and also to neuronal activity in higher centres in the brain. This microglial response leads to the production and release of several proinflammatory mediators which contribute to neuronal sensitisation under neuropathic pain states. In this review, we collect evidence demonstrating the critical role played by the Fractalkine/CX3CR1 signalling pathway in neuron-to-microglia communication in neuropathic pain states and explore how strategies that include components of this pathway offer opportunities for innovative targets for neuropathic pain.

Connecting Neuroinflammation and Neurodegeneration in Multiple Sclerosis: Are Oligodendrocyte Precursor Cells a Nexus of Disease?

The pathology in neurodegenerative diseases is often accompanied by inflammation. It is well-known that many cells within the central nervous system (CNS) also contribute to ongoing neuroinflammation, which can promote neurodegeneration. Multiple sclerosis (MS) is both an inflammatory and neurodegenerative disease in which there is a complex interplay between resident CNS cells to mediate myelin and axonal damage, and this communication network can vary depending on the subtype and chronicity of disease. Oligodendrocytes, the myelinating cell of the CNS, and their precursors, oligodendrocyte precursor cells (OPCs), are often thought of as the targets of autoimmune pathology during MS and in several animal models of MS; however, there is emerging evidence that OPCs actively contribute to inflammation that directly and indirectly contributes to neurodegeneration. Here we discuss several contributors to MS disease progression starting with lesion pathology and murine models amenable to studying particular aspects of disease. We then review how OPCs themselves can play an active role in promoting neuroinflammation and neurodegeneration, and how other resident CNS cells including microglia, astrocytes, and neurons can impact OPC function. Further, we outline the very complex and pleiotropic role(s) of several inflammatory cytokines and other secreted factors classically described as solely deleterious during MS and its animal models, but in fact, have many neuroprotective functions and promote a return to homeostasis, in part via modulation of OPC function. Finally, since MS affects patients from the onset of disease throughout their lifespan, we discuss the impact of aging on OPC function and CNS recovery. It is becoming clear that OPCs are not simply a bystander during MS progression and uncovering the active roles they play during different stages of disease will help uncover potential new avenues for therapeutic intervention.

Neuroimmune disruptions from naturally occurring levels of mycotoxins.

Substantial pieces of evidence support the potential of exogenous toxins in disrupting neuroimmune homeostasis. It appears that mycotoxins are one of the noticeable sources of naturally occurring substances dysregulating the immune system, which involves the physiology of many organs, such as the central nervous system (CNS). The induction of inflammatory responses in microglial cells and astrocytes, the CNS resident cells with immunological characteristics, could interrupt the hemostasis upon even with low-level exposure to mycotoxins. The inevitable widespread occurrence of a low level of mycotoxins in foods and feed is likely increasing worldwide, predisposing individuals to potential neuroimmunological dysregulations. This paper reviews the current understanding of mycotoxins' neuro-immunotoxic features under low-dose exposure and the possible ways for detoxification and clearance as a perspective.

Direct and indirect effects of microbiota-derived metabolites on neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are highly influenced by changes in the microbiota and of microbiota-derived metabolites, including short chain fatty acids, bile acids, and tryptophan derivatives. This review will discuss the effects of microbiota-derived metabolites on neuroinflammation driven by central nervous system-resident cells and peripheral immune cells, and their influence on outcomes of EAE and MS.

PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity.

Synapses are the functional units of the brain. They form specific contact points that drive neuronal communication and are highly plastic in their strength, density, and shape. A carefully orchestrated balance between synaptogenesis and synaptic pruning, i.e., the elimination of weak or redundant synapses, ensures adequate synaptic density. An imbalance between these two processes lies at the basis of multiple neuropathologies. Recent evidence has highlighted the importance of glia-neuron interactions in the synaptic unit, emphasized by glial phagocytosis of synapses and local excretion of inflammatory mediators. These findings warrant a closer look into the molecular basis of cell-signaling pathways in the different brain cells that are related to synaptic plasticity. In neurons, intracellular second messengers, such as cyclic guanosine or adenosine monophosphate (cGMP and cAMP, respectively), are known mediators of synaptic homeostasis and plasticity. Increased levels of these second messengers in glial cells slow down inflammation and neurodegenerative processes. These multi-faceted effects provide the opportunity to counteract excessive synapse loss by targeting cGMP and cAMP pathways in multiple cell types. Phosphodiesterases (PDEs) are specialized degraders of these second messengers, rendering them attractive targets to combat the detrimental effects of neurological disorders. Cellular and subcellular compartmentalization of the specific isoforms of PDEs leads to divergent downstream effects for these enzymes in the various central nervous system resident cell types. This review provides a detailed overview on the role of PDEs and their inhibition in the context of glia-neuron interactions in different neuropathologies characterized by synapse loss. In doing so, it provides a framework to support future research towards finding combinational therapy for specific neuropathologies.

Organotypic Brain Slice Culture Microglia Exhibit Molecular Similarity to Acutely-Isolated Adult Microglia and Provide a Platform to Study Neuroinflammation.

Microglia are central nervous system (CNS) resident immune cells that have been implicated in neuroinflammatory pathogenesis of a variety of neurological conditions. Their manifold context-dependent contributions to neuroinflammation are only beginning to be elucidated, which can be attributed in part to the challenges of studying microglia in vivo and the lack of tractable in vitro systems to study microglia function. Organotypic brain slice cultures offer a tissue-relevant context that enables the study of CNS resident cells and the analysis of brain slice microglial phenotypes has provided important insights, in particular into neuroprotective functions. Here we use RNA sequencing, direct digital quantification of gene expression with nCounter® technology and targeted analysis of individual microglial signature genes, to characterize brain slice microglia relative to acutely-isolated counterparts and 2-dimensional (2D) primary microglia cultures, a widely used in vitro surrogate. Analysis using single cell and population-based methods found brain slice microglia exhibited better preservation of canonical microglia markers and overall gene expression with stronger fidelity to acutely-isolated adult microglia, relative to in vitro cells. We characterized the dynamic phenotypic changes of brain slice microglia over time, after plating in culture. Mechanical damage associated with slice preparation prompted an initial period of inflammation, which resolved over time. Based on flow cytometry and gene expression profiling we identified the 2-week timepoint as optimal for investigation of microglia responses to exogenously-applied stimuli as exemplified by treatment-induced neuroinflammatory changes observed in microglia following LPS, TNF and GM-CSF addition to the culture medium. Altogether these findings indicate that brain slice cultures provide an experimental system superior to in vitro culture of microglia as a surrogate to investigate microglia functions, and the impact of soluble factors and cellular context on their physiology.

CNS Macrophages and Infant Infections.

The central nervous system (CNS) harbors its own immune system composed of microglia in the parenchyma and CNS-associated macrophages (CAMs) in the perivascular space, leptomeninges, dura mater, and choroid plexus. Recent advances in understanding the CNS resident immune cells gave new insights into development, maturation and function of its immune guard. Microglia and CAMs undergo essential steps of differentiation and maturation triggered by environmental factors as well as intrinsic transcriptional programs throughout embryonic and postnatal development. These shaping steps allow the macrophages to adapt to their specific physiological function as first line of defense of the CNS and its interfaces. During infancy, the CNS might be targeted by a plethora of different pathogens which can cause severe tissue damage with potentially long reaching defects. Therefore, an efficient immune response of infant CNS macrophages is required even at these early stages to clear the infections but may also lead to detrimental consequences for the developing CNS. Here, we highlight the recent knowledge of the infant CNS immune system during embryonic and postnatal infections and the consequences for the developing CNS.

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens.

Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long-term neurological deficits in survivors. Resident CNS cell types, such as astrocytes and microglia, are known to produce key inflammatory and antiviral mediators following infection with neurotropic DNA viruses. However, the mechanisms by which glia mediate such responses remain poorly understood. Recently, a class of intracellular pattern recognition receptors (PRRs), collectively known as DNA sensors, have been identified in both leukocytic and non-leukocytic cell types. The ability of such DNA sensors to initiate immune mediator production and contribute to infection resolution in the periphery is increasingly recognized, but our understanding of their role in the CNS remains limited at best. In this review, we describe the evidence for the expression and functionality of DNA sensors in resident brain cells, with a focus on their role in neurotropic virus infections. The available data indicate that glia and neurons can constitutively express, and/or can be induced to express, various disparate DNA sensing molecules previously described in peripheral cell types. Furthermore, multiple lines of investigation suggest that these sensors are functional in resident CNS cells and are required for innate immune responses to viral infections. However, it is less clear whether DNA sensormediated glial responses are beneficial or detrimental, and the answer to this question appears to dependent on the context of the infection with regard to the identity of the pathogen, host cell type, and host species. Defining such parameters will be essential if we are to successfully target these molecules to limit damaging inflammation while allowing beneficial host responses to improve patient outcomes.

Targeting Chemokines and Chemokine Receptors in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is an immune-mediated and neurodegenerative disorder that results in inflammation and demyelination of the central nervous system (CNS). MS symptoms include walking difficulties, visual weakening, as well as learning and memory impairment, thus affecting the quality of the patient’s life. Chemokines and chemokine receptors are expressed on the immune cells as well as the CNS resident cells. Several sets of chemokine receptors and their ligands tend to be pathogenic players in MS, including CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL17, CCL19, CCL21, CCL22, CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, and CXCL16. Furthermore, current modulatory drugs that are used in the treatment of MS and its animal model, the experimental autoimmune encephalomyelitis (EAE), affect the expression of several chemokine and chemokine receptors. In this review, we highlight the pathogenic roles of chemokines and their receptors as well as utilizing them as potential therapeutic targets through selective agents, such as specific antibodies and receptor blockers, or indirectly through MS or EAE immunomodulatory drugs.

Abstract 320: 3D-bioprinting of biomimetic multicellular glioblastoma tissues enable modeling of tumor-immune interactions

Abstract The glioblastoma is a complex ecosystem with multiple cell types and an extracellular matrix (ECM) unique to the brain. Dynamic interactions between tumor cells and other non-neoplastic cell types drive the progression of cancer and continuously remodel the local microenvironment. Some major non-neoplastic players in the glioblastoma microenvironment include blood vessels that support tumor growth, several resident central nervous system (CNS) cells such as astrocytes, neurons, and microglia, as well as tumor-associated macrophages, the most substantial non-neoplastic component of glioblastoma. While animal models retain the genomic signature and transcriptome of the original patient tumor tissue, the use of immunocompromised animals inherently limits investigation of the role of immune components within the glioblastoma tissue. Here, we developed a rapid 3D-bioprinting method to construct a clinically relevant multicellular in vitro model to recapitulate the complexity of the glioblastoma microenvironment. The 3D models made of brain-specific materials were constructed with a central core of glioblastoma stem cells, with or without macrophages, surrounded by the resident CNS cells, which served to mimic the brain parenchyma surrounding the tumor tissue. Gene expression and transcriptome analysis demonstrated that both the glioblastoma stem cells and the macrophage precursors responded to the 3D-bioprinted glioblastoma microenvironment and better resembled their counterparts in patient tumor tissue compared to sphere or suspension culture. Furthermore, the four-cell model with macrophages closely resembled patient transcriptional profiles predictive of patient prognosis and drug sensitivity, and better recapitulated the glioblastoma invasiveness and stemness compared to three-cell models without macrophages or sphere cultures. Finally, the 3D-bioprinted models also enabled whole genome CRISPR screening to identify unique functional dependencies not identified in sphere culture controls. The 3D-bioprinting method is highly scalable and reproducible. The multicellular glioblastoma model combines fine spatial control of brain-specific materials and multiple cell types to create a sophisticated human species-matched model that contains both neoplastic and non-neoplastic regions. Citation Format: Min Tang, Qi Xie, Ryan C. Gimple, Briana C. Prager, Zhixin Qiu, Jacob Schimelman, Pengrui Wang, Derrick Lee, Aaron Yu, Tyler E. Miller, Reilly L. Kidwell, Xueyi Wan, Jing Tang, Trevor Tam, Jing Tian, Bingjie Sun, Shaochen Chen, Jeremy Rich. 3D-bioprinting of biomimetic multicellular glioblastoma tissues enable modeling of tumor-immune interactions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 320.

SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms.

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

Cladribine modifies functional properties of microglia.

SummaryCladribine (CdA), an oral prodrug approved for the treatment of relapsing multiple sclerosis, selectively depletes lymphocytes. CdA passes the blood–brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. We examined if CdA modifies the phenotype and function of naive and activated primary mouse microglia, when applied in the concentrations 0·1–1 μM that putatively overlap human cerebrospinal fluid (CSF) concentrations. Primary microglia cultures without stimulation or in the presence of proinflammatory lipopolysaccharide (LPS) or anti‐inflammatory interleukin (IL)‐4 were treated with different concentrations of CdA for 24 h. Viability was assessed by MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] assay. Phagocytotic ability and morphology were examined by flow cytometry and random migration using IncuCyte Zoom and TrackMate. Change in gene expression was examined by quantitative polymerase chain reaction (qPCR) and protein secretion by Meso Scale Discovery. We found that LPS and IL‐4 up‐regulated deoxycytidine kinase (DCK) expression. Only activated microglia were affected by CdA, and this was unrelated to viability. CdA 0·1–1 μM significantly reduced granularity, phagocytotic ability and random migration of activated microglia. CdA 10 μM increased the IL‐4‐induced gene expression of arginase 1 (Arg1) and LPS‐induced expression of IL‐1β, tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS) and Arg1, but protein secretion remained unaffected. CdA 10 μM potentiated the increased expression of anti‐inflammatory TNF receptor 2 (TNF‐R2) but not TNF‐R1 induced by LPS. This suggests that microglia acquire a less activated phenotype when treated with 0·1–1 μM CdA that putatively overlaps human CSF concentrations. This may be related to the up‐regulated gene expression of DCK upon activation, and suggests a potential alternative mechanism of CdA with direct effect on CNS resident cells.

Comprehensive Analysis of the Immune and Stromal Compartments of the CNS in EAE Mice Reveal Pathways by Which Chloroquine Suppresses Neuroinflammation.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are neuroinflammatory diseases of the central nervous system (CNS), where leukocytes and CNS resident cells play important roles in disease development and pathogenesis. The antimalarial drug chloroquine (CQ) has been shown to suppress EAE by modulating dendritic cells (DCs) and Th17 cells. However, the mechanism of action by which CQ modulates EAE is far from being elucidated. Here, we comprehensively analyzed the CNS of CQ and PBS-treated EAE mice to identify and characterize the cells that are affected by CQ. Our results show that leukocytes are largely modulated by CQ and have a reduction in the expression of inflammatory markers. Intriguingly, CQ vastly modulated the CNS resident cells astrocytes, oligodendrocytes (OLs) and microglia (MG), with the latter producing IL-10 and IL-12p70. Overall, our results show a panoramic view of the cellular components that are affect by CQ and provide further evidence that drug repurposing of CQ will be beneficial to MS patients.

Exosomes secreted from microglia during chronic virus infection can induce demyelinating disease

Abstract Theiler’s murine encephalomyelitis virus (TMEV) induced demyelinating disease is a murine model for multiple sclerosis (MS). TMEV persists in microglia and leads to development of chronic progressive demyelinating disease associated with an inflammatory immune response in the central nervous system (CNS) of susceptible mice. TMEV-infected microglia secrete innate immune cytokines, chemokines, and effector molecules associated with development and progression of demyelinating disease. Recently, we have found that TMEV-infected microglia secrete nanovesicles called exosomes that contain and transfer viral RNA to bystander cells in the CNS. Our present studies show that exosomes secreted by microglia during TMEV-induced demyelinating disease (63–98dpi) contain viral RNA/genome that can be taken up by other CNS resident cells, transferring the viral RNA. More importantly, these exosomes could induce the bystander CNS cells to express inflammatory cytokines and chemokines. When administered into naïve mice, exosomes secreted by microglia during TMEV-induced demyelinating disease promoted MS-like pathology including microglia activation and demyelination in the spinal cord. These results suggest that exosomes secreted by infected microglia may directly contribute to the development and progression of demyelinating disease.

Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase

BackgroundSema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS.MethodsWe adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-β (n = 38) in all of relapsing-remitting multiple sclerosis (RRMS) patients enrolled in this study.ResultsSema4A KO recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a significant reduction in the clinical score compared to the WT recipient mice. However, Sema4A KO recipient mice showed similar disease activity to the WT recipient mice when transferred with Th1-skewed encephalitogenic T cells. Bone marrow chimeric study indicated that Sema4A expressed on hematopoietic cells, but not the CNS resident cells, are responsible for augmenting Th17-mediated neuroinflammation. Additionally, in contrast to comparable IFN-γ levels, IL-17A is significantly higher in RRMS patients with high Sema4A level than those with low Sema4A patients with high Sema4A levels showed earlier disease onset, more severe disease activity and IFN-β unresponsiveness than those with low Sema4A levels.ConclusionsSema4A is involved not only in the Th cell priming but also in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase, which could contribute to the higher disease activity observed in RRMS patients with high serum Sema4A levels.

Supportive roles of brain macrophages in CNS metastases and assessment of new approaches targeting their functions.

Metastases to the central nervous system (CNS) occur frequently in adults and their frequency increases with the prolonged survival of cancer patients. Patients with CNS metastases have short survival, and modern therapeutics, while effective for extra-cranial cancers, do not reduce metastatic burden. Tumor cells attract and reprogram stromal cells, including tumor-associated macrophages that support cancer growth by promoting tissue remodeling, invasion, immunosuppression and metastasis. Specific roles of brain resident and infiltrating macrophages in creating a pre-metastatic niche for CNS invading cancer cells are less known. There are populations of CNS resident innate immune cells such as: parenchymal microglia and non-parenchymal, CNS border-associated macrophages that colonize CNS in early development and sustain its homeostasis. In this study we summarize available data on potential roles of different brain macrophages in most common brain metastases. We hypothesize that metastatic cancer cells exploit CNS macrophages and their cytoprotective mechanisms to create a pre-metastatic niche and facilitate metastatic growth. We assess current pharmacological strategies to manipulate functions of brain macrophages and hypothesize on their potential use in a therapy of CNS metastases. We conclude that the current data strongly support a notion that microglia, as well as non-parenchymal macrophages and peripheral infiltrating macrophages, are involved in multiple stages of CNS metastases. Understanding their contribution will lead to development of new therapeutic strategies.