Intracerebral haemorrhage is inadequately controlled by current treatments, requiring new solutions to improve the prognosis. Following the primary injury, a proinflammatory cascade in the ...perihaematomal region, composed of activated resident microglia and astrocytes and infiltrated leucocytes, propagates neural cell death. The protracted nature of neuroinflammation in intracerebral haemorrhage provides a window of opportunity for therapies to subdue the undesired consequences. In animal models and early clinical trials in intracerebral haemorrhage, several drugs have reduced detrimental neuroinflammation without substantial compromise of the beneficial reparative aspects of an inflammatory response. Potential strategies include controlling excessive harmful neuroinflammation with minocycline, sphingosine-1-phosphate receptor modulators, and statins after a brain haemorrhage. The quick initiation of these drugs, particularly in high systemic doses, could be key to counteracting the evolving secondary injury in people with intracerebral haemorrhage and provides a promising way in which the poor prognosis of intracerebral haemorrhage might one day be counteracted.
Microglia are implicated in all stages of multiple sclerosis (MS). Microglia alterations are detected by positron emission tomography in people living with MS prior to the formation of structural ...lesions determined through magnetic resonance imaging. In histological specimens, clusters of microglia form in normal-appearing tissue likely predating the development of lesions. Features of degeneration-associated/pro-inflammatory states of microglia increase with chronicity of MS. However, microglia play many beneficial roles including the removal of neurotoxins and in fostering repair. The protector-gone-rogue microglia in MS is featured herein. We consider mechanisms of microglia neurotoxicity and discuss factors, including aging, osteopontin, and iron metabolism, that cause microglia to lose their protective states and become injurious. We evaluate medications to affect microglia in MS, such as the emerging class of Bruton’s tyrosine kinase inhibitors. The framework of microglia-turned-destroyers may instigate new approaches to counter microglia-driven neurodegeneration in MS.
The benefits of microglia appear to be derailed in multiple sclerosis where they assume injurious roles. Yong reviews the protector-gone-rogue activities of microglia, considers the mechanisms underlying this switch, and discusses medications to normalize microglia in multiple sclerosis.
The prognosis of intracerebral haemorrhage continues to be devastating despite much research into this condition. A prominent feature of intracerebral haemorrhage is neuroinflammation, particularly ...the excessive representation of pro-inflammatory CNS-intrinsic microglia and monocyte-derived macrophages that infiltrate from the circulation. The pro-inflammatory microglia/macrophages produce injury-enhancing factors, including inflammatory cytokines, matrix metalloproteinases and reactive oxygen species. Conversely, the regulatory microglia/macrophages with potential reparative and anti-inflammatory roles are outcompeted in the early stages after intracerebral haemorrhage, and their beneficial roles appear to be overwhelmed by pro-inflammatory microglia/macrophages. In this review, we describe the activation of microglia/macrophages following intracerebral haemorrhage in animal models and clinical subjects, and consider their multiple mechanisms of cellular injury after haemorrhage. We review strategies and medications aimed at suppressing the pro-inflammatory activities of microglia/macrophages, and those directed at elevating the regulatory properties of these myeloid cells after intracerebral haemorrhage. We consider the translational potential of these medications from preclinical models to clinical use after intracerebral haemorrhage injury, and suggest that several approaches still lack the experimental support necessary for use in humans. Nonetheless, the preclinical data support the use of deactivator or inhibitor of pro-inflammatory microglia/macrophages, whilst enhancing the regulatory phenotype, as part of the therapeutic approach to improve the prognosis of intracerebral haemorrhage.
Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To ...overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.
Immune cells mediate critical inflammatory and neurodegenerative processes in the CNS in individuals with multiple sclerosis (MS). In MS, activated microglia, border-associated macrophages and ...monocyte-derived macrophages in the CNS can encounter T cells that have infiltrated the brain parenchyma from the circulation. Although microglia and T cells both contribute to normal CNS development and homeostasis, evidence suggests that the meeting of activated microglia and macrophages with encephalitogenic T cells exacerbates their capacity to inflict injury. This crosstalk involves many cell-surface molecules, cytokines and neurotoxic factors. In this Review, we summarize the mechanisms and consequences of T cell-microglia interactions as identified with in vitro experiments and animal models, and discuss the challenges that arise when translating this preclinical knowledge to MS in humans. We also consider therapeutic approaches to MS of which the mechanisms involve prevention or modulation of T cell and microglia responses and their interactions.
In contrast to the multiple disease-modifying therapies that are available for relapsing-remitting multiple sclerosis (MS), the therapeutic options for progressive MS (PMS) are limited. Recent ...advances in our understanding of the neuroimmunology of PMS, including the mechanisms that drive slowly expanding lesions, have fuelled optimism for improved treatment of this condition. In this Review, we highlight the commonly observed neuropathology of PMS and discuss the associated mechanisms of CNS injury. We then apply this knowledge to formulate criteria for therapeutic efficacy in PMS, beginning with the need for early treatment owing to the substantial neuropathology that is already present at the initial clinical presentation. Other requirements include: antagonism of neuroaxonal injury mediators such as pro-inflammatory microglia and lymphocytes; remediation of oxidative stress resulting from iron deposition and mitochondrial dysfunction; and promotion of neuroprotection through remyelination. We consider whether current disease-modifying therapies for relapsing-remitting MS meet the criteria for successful therapeutics in PMS and suggest that the evidence favours the early introduction of sphingosine 1-phosphate receptor modulators. Finally, we weigh up emerging medications, including repurposed generic medications and Bruton's tyrosine kinase inhibitors, against these fundamental criteria. In this new therapeutic era in PMS, success depends collectively on understanding disease mechanisms, drug characteristics (including brain penetration) and rational use.
Remyelination failure contributes to axonal loss and progression of disability in multiple sclerosis. The failed repair process could be due to ongoing toxic neuroinflammation and to an inhibitory ...lesion microenvironment that prevents recruitment and/or differentiation of oligodendrocyte progenitor cells into myelin-forming oligodendrocytes. The extracellular matrix molecules deposited into lesions provide both an altered microenvironment that inhibits oligodendrocyte progenitor cells, and a fuel that exacerbates inflammatory responses within lesions. In this review, we discuss the extracellular matrix and where its molecules are normally distributed in an uninjured adult brain, specifically at the basement membranes of cerebral vessels, in perineuronal nets that surround the soma of certain populations of neurons, and in interstitial matrix between neural cells. We then highlight the deposition of different extracellular matrix members in multiple sclerosis lesions, including chondroitin sulphate proteoglycans, collagens, laminins, fibronectin, fibrinogen, thrombospondin and others. We consider reasons behind changes in extracellular matrix components in multiple sclerosis lesions, mainly due to deposition by cells such as reactive astrocytes and microglia/macrophages. We next discuss the consequences of an altered extracellular matrix in multiple sclerosis lesions. Besides impairing oligodendrocyte recruitment, many of the extracellular matrix components elevated in multiple sclerosis lesions are pro-inflammatory and they enhance inflammatory processes through several mechanisms. However, molecules such as thrombospondin-1 may counter inflammatory processes, and laminins appear to favour repair. Overall, we emphasize the crosstalk between the extracellular matrix, immune responses and remyelination in modulating lesions for recovery or worsening. Finally, we review potential therapeutic approaches to target extracellular matrix components to reduce detrimental neuroinflammation and to promote recruitment and maturation of oligodendrocyte lineage cells to enhance remyelination.
The matrix metalloproteinases and related A disintegrin and metalloproteinase enzymes are implicated in various diseases of the nervous system. However, metalloproteinases are increasingly being ...recognized as having beneficial roles during nervous system development and following injury. This review discusses general principles that govern the expression of metalloproteinases in the nervous system and their detrimental outcomes. It then focuses on the roles of metalloproteinases and their mechanisms in regulating neurogenesis, myelin formation and axonal growth. It is clear that metalloproteinases are important determinants in enabling recovery from injury to the nervous system.
Inflammation of the nervous system (neuroinflammation) is now recognized as a hallmark of virtually all neurological disorders. In neuroinflammatory conditions such as multiple sclerosis, there is ...prominent infiltration and a long-lasting representation of various leukocyte subsets in the central nervous system (CNS) parenchyma. Even in classic neurodegenerative disorders, where such immense inflammatory infiltrates are absent, there is still evidence of activated CNS-intrinsic microglia. The consequences of excessive and uncontrolled neuroinflammation are injury and death to neural elements, which manifest as a heterogeneous set of neurological symptoms. However, it is now readily acknowledged, due to instructive studies from the peripheral nervous system and a large body of CNS literature, that aspects of the neuroinflammatory response can be beneficial for CNS outcomes. The recognized benefits of inflammation to the CNS include the preservation of CNS constituents (neuroprotection), the proliferation and maturation of various neural precursor populations, axonal regeneration, and the reformation of myelin on denuded axons. Herein, we highlight the benefits of neuroinflammation in fostering CNS recovery after neural injury using examples from multiple sclerosis, traumatic spinal cord injury, stroke, and Alzheimer's disease. We focus on CNS regenerative responses, such as neurogenesis, axonal regeneration, and remyelination, and discuss the mechanisms by which neuroinflammation is pro-regenerative for the CNS. Finally, we highlight treatment strategies that harness the benefits of neuroinflammation for CNS regenerative responses.
Discussions of multiple sclerosis (MS) pathophysiology tend to focus on T cells and B cells of the adaptive immune response. The innate immune system is less commonly considered in this context, ...although dendritic cells, monocytes, macrophages and microglia - collectively referred to as myeloid cells - have prominent roles in MS pathogenesis. These populations of myeloid cells function as antigen-presenting cells and effector cells in neuroinflammation. Furthermore, a vicious cycle of interactions between T cells and myeloid cells exacerbates pathology. Several disease-modifying therapies are now available to treat MS, and insights into their mechanisms of action have largely focused on the adaptive immune system, but these therapies also have important effects on myeloid cells. In this Review, we discuss the evidence for the roles of myeloid cells in MS and the experimental autoimmune encephalomyelitis model of MS, and consider how interactions between myeloid cells and T cells and/or B cells promote MS pathology. Finally, we discuss the direct and indirect effects of existing MS medications on myeloid cells.
PDF
