Glioma cells in situ are surrounded by microglia, suggesting the potential of glioma-microglia interactions to produce various outcomes. As chemokines are important mediators of cell-cell ...communication, we sought first to identify commonly expressed chemokines in 16 human glioma lines. We found CCL2 (macrophage chemoattractant protein-1) messenger RNA to be expressed by the majority of glioma lines. However, these lines did not express the CCL2 receptor, CCR2, which was found on microglia. Next, we overexpressed CCL2 in the U87 glioma line, which has low basal level of CCL2, to investigate the hypothesis that glioma-secreted CCL2 interacts with microglia to affect glioma growth. Stable clones with 10- to 12-fold elevation of CCL2 have similar growth rate and invasive capacity as vector controls when cultured in isolation. However, in coculture with microglia in a three-dimensional collagen gel matrix, the invasiveness of CCL2-overexpressing clones was increased. Gene array analyses were then undertaken and they revealed that interleukin (IL)-6 was consistently increased in the coculture. Recombinant IL-6 enhanced the invasiveness of glioma cells when these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the microglia-stimulated glioma invasiveness. Finally, we found that human glioma specimens in situ contained IL-6 immunoreactivity that was expressed on CD68+ cells. This study has uncovered a mechanism by which glioma cells exploit microglia for increased invasiveness. Specifically, glioma-derived CCL2 acts upon CCR2-bearing microglia, which then produces IL-6 to stimulate gliomas. The CCL2/CCR2/IL-6 loop is a potential therapeutic target for the currently incurable malignant gliomas.
Multiple sclerosis is characterized by inflammatory activity that results in destruction of the myelin sheaths that enwrap axons. The currently available medications for multiple sclerosis are ...predominantly immune-modulating and do not directly promote repair. White matter regeneration, or remyelination, is a new and exciting potential approach to treating multiple sclerosis, as remyelination repairs the damaged regions of the central nervous system. A wealth of new strategies in animal models that promote remyelination, including the repopulation of oligodendrocytes that produce myelin, has led to several clinical trials to test new reparative therapies. In this Review, we highlight the biology of, and obstacles to, remyelination. We address new strategies to improve remyelination in preclinical models, highlight the therapies that are currently undergoing clinical trials and discuss the challenges of objectively measuring remyelination in trials of repair in multiple sclerosis.
An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate ...remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow-derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired.
•Vildagliptin performs neuroprotective functions following intracerebral hemorrhage in mice.•Vildagliptin inhibits brain cell apoptosis and ferroptosis after intracerebral hemorrhage in ...mice.•Vildagliptin suppresses neuroinflammation following intracerebral hemorrhage in mice.
Intracerebral hemorrhage (ICH) is a fatal health problem which lacks effective treatment. The apoptosis caused by hematoma constituents, and the ferroptosis due to iron overload, are prominent contributors of neurologic impairment after ICH. Targeting cell death pathways may thus be a therapeutic strategy for neuroprotection and functional recovery in ICH. Vildagliptin (Vilda), a dipeptidyl peptidase (DPP)-4 inhibitor, has been reported to have potent anti-apoptosis and anti-ferroptotic capacity. However, it is not clear whether Vilda has anti-cell death efficacy in ICH. In the present study, the potential neuroprotective effect of Vilda in ICH mice was investigated. Mice were randomly divided into three groups: sham, ICH + saline or ICH + Vilda. ICH was induced by collagenase type VII micro-injection into the right basal ganglia. Vilda (50 mg/kg/day; gavage) daily treatment for 3 days after ICH improved neurological deficit scores, reduced hematoma volume, and inhibited degeneration of neurons. The activation of microglia/macrophages and infiltration of neutrophil were restrained by Vilda. Moreover, Vilda attenuated brain cell apoptosis as determined by TUNEL staining, raised Bcl-2 protein level, and simultaneously suppressed Bax as validated by western blots. In addition, Vilda reduced malondialdehyde level, elevated glutathione peroxidase brain content, and alleviated iron deposition at 3 days after ICH in mice. In conclusion, Vilda exerts neuroprotective effects in ICH, at least in part by inhibiting neuroinflammation, and preventing neuronal apoptosis and ferroptosis following ICH.
Glioblastoma is an aggressive and incurable primary brain tumor. While the blockade of immune checkpoints leads to reversal of T cell exhaustion in many cancers, the efficacy of this therapy in ...glioblastoma requires further consideration of the brain microenvironment beyond T cell activity. Neural cells are crucially dependent on glucose for survival, and tumor cells rabidly consume glucose; the glucose-deprived microenvironment further elevates immune checkpoint molecules to benefit tumor growth and exacerbate T cell exhaustion. We review here how immune checkpoints drive exhaustion in T cells while favoring tumor metabolism, and discuss how glucose competition in the unique CNS milieu is an important consideration to improve the outcomes of immune checkpoint blockade in glioblastoma.
Inflammation of the central nervous system (CNS) (neuroinflammation) is now recognized to be a feature of all neurological disorders. In multiple sclerosis, there is prominent infiltration of various ...leukocyte subsets into the CNS. Even when there is no significant inflammatory infiltrates, such as in Parkinson or Alzheimer disease, there is intense activation of microglia with resultant elevation of many inflammatory mediators within the CNS. An extensive dataset describes neuroinflammation to have detrimental consequences, but results emerging largely over the past decade have indicated that aspects of the inflammatory response are beneficial for CNS outcomes. Benefits of neuroinflammation now include neuroprotection, the mobilization of neural precursors for repair, remyelination, and even axonal regeneration. The findings that neuroinflammation can be beneficial should not be surprising as a properly directed inflammatory response in other tissues is a natural healing process after an insult. In this article, we review the data that highlight the dual aspects of neuroinflammation in being a hindrance on the one hand but also a significant help for recovery of the CNS on the other. We consider how the inflammatory response may be beneficial or injurious, and we describe strategies to harness the beneficial aspects of neuroinflammation.
B cells represent a relatively minor cell population within both the healthy and diseased central nervous system (CNS), yet they can have profound effects. This is emphasized in multiple sclerosis, ...in which B cell-depleting therapies are arguably the most efficacious treatment for the condition. In this Review, we discuss how B cells enter and persist in the CNS and how, in many neurological conditions, B cells concentrate within CNS barriers but are rarely found in the parenchyma. We highlight how B cells can contribute to CNS pathology through antibody secretion, antigen presentation and secretion of neurotoxic molecules, using examples from CNS tumours, CNS infections and autoimmune conditions such as neuromyelitis optica and, in particular, multiple sclerosis. Overall, understanding common and divergent principles of B cell accumulation and their effects within the CNS could offer new insights into treating these devastating neurological conditions.
Neurodegeneration drives the progression of many neurological diseases. Inflammation and oxidative stress occurring in the CNS promote lipid peroxidation, leading to the generation of oxidized ...phospholipids such as oxidized phosphatidylcholines (OxPCs). OxPCs have been proposed as biomarkers of oxidative stress, where their detection in lesions in multiple sclerosis (MS), frontotemporal lobe dementia, spinal cord injury, and amyotrophic lateral sclerosis (ALS) implies that oxidative insult had occurred. However, recent findings highlight OxPCs as potent neurotoxic species requiring neutralization by microglia. Here, we summarize the science of OxPCs, including lessons from non-CNS diseases. We discuss the potential of OxPCs as common drivers of injury across neurological conditions and encourage investigations of OxPCs as novel neurotoxins.
Lipid peroxidation products such as oxidized phospholipids are associated with inflammation and neurodegeneration in diseases of the CNS.Oxidized phosphatidylcholines (OxPCs) are among the best-understood class of oxidized phospholipids. They are found in lesions of multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal lobe dementia, and spinal cord injury.In the mouse spinal cord, OxPC deposition causes demyelination and neurodegeneration, and requires triggering receptor expressed on myeloid cells 2 (TREM2)-expressing microglia for clearance.OxPCs are cytotoxic and promote inflammation and pathology in multiple non-CNS diseases. Additional investigations to understand OxPC heterogeneity, functions, and mechanisms in the CNS may uncover new therapeutics for neurodegenerative diseases.
The repair of myelin, termed remyelination, is a regenerative process that occurs within the central nervous system in conditions such as multiple sclerosis. Remyelination is enabled by ...oligodendrocytes that mature from oligodendrocyte precursor cells. Many factors influence the biology of oligodendrocytes and their capacity to reform myelin, and considerable evidence now implicates the extracellular matrix within the injured central nervous system as a major modifier of remyelination. Herein, we review current knowledge of components of the brain extracellular matrix that are beneficial or inhibitory for oligodendrocyte recruitment and maturation, and for their capacity to remyelinate where evidence exists. We highlight the detrimental roles of the chondroitin sulfate proteoglycans in remyelination and discuss approaches to alter the brain extracellular matrix for the wellbeing of oligodendrocytes and their capacity for myelin regeneration.
Preclinical studies have attributed neuroprotective properties to the antibiotic minocycline. Animal studies and early clinical trials support its use in several neurological diseases. In animal ...spinal cord injury models, minocycline improved neurological and histological outcomes, reduced neuronal and oligodendroglial apoptosis, decreased microglial activation and reduced inflammation. A single-centre, human, double-blind, randomized, placebo-controlled study of minocycline administration after spinal cord injury was undertaken for the purposes of dose optimization, safety assessment and to estimate outcome changes and variance. Neurological, functional, pharmacological and adverse event outcomes were compared between subjects administered 7 days of intravenous minocycline (n = 27) or placebo (n = 25) after acute traumatic spinal cord injury. The secondary outcome used to assess neurological differences between groups that may warrant further investigation was motor recovery over 1 year using the American Spinal Cord Injury Association examination. Recruitment and analyses were stratified by injury severity and injury location a priori given the expected influence of these on the sensitivity of the motor exam. Minocycline administered at higher than previously reported human doses produced steady-state concentrations of 12.7 µg/ml (95% confidence interval 11.6-13.8) in serum and 2.3 µg/ml (95% confidence interval 2.1-2.5) in cerebrospinal fluid, mimicking efficacious serum levels measured in animal studies. Transient elevation of serum liver enzymes in one patient was the only adverse event likely related to the study drug. Overall, patients treated with minocycline experienced six points greater motor recovery than those receiving placebo (95% confidence interval -3 to 14; P = 0.20, n = 44). No difference in recovery was observed for thoracic spinal cord injury (n = 16). A difference of 14 motor points that approached significance was observed in patients with cervical injury (95% confidence interval 0-28; P = 0.05, n = 25). Patients with cervical motor-incomplete injury may have experienced a larger difference (results not statistically significant, n = 9). Functional outcomes exhibited differences that lacked statistical significance but that may be suggestive of improvement in patients receiving the study drug. The minocycline regimen established in this study proved feasible, safe and was associated with a tendency towards improvement across several outcome measures. Although this study does not establish the efficacy of minocycline in spinal cord injury the findings are encouraging and warrant further investigation in a multi-centre phase III trial. ClinicalTrials.gov number NCT00559494.
PDF
