Neuroinflammation is common to various diseases of the central nervous system (CNS), but its imprecise definition has led to many misconceptions in research and clinical approaches. It is now ...recognized that neuroinflammation in chronic neurodegenerative conditions, including Alzheimer's disease (AD) and age-related dementia, is distinct from the inflammation that accompanies relapsing–remitting multiple sclerosis (RRMS), and its experimental animal model, experimental autoimmune encephalomyelitis (EAE). Here, we discuss the discrete features of inflammation in different CNS pathologies, given the current understanding of the CNS–immune crosstalk; the roles of the immune cells that are involved, their phenotypes, and their location and route of entry to the CNS. Understanding the term neuroinflammation to encompass a broad range of disease-specific conditions is essential for finding effective therapeutic approaches for these pathologies.
Inflammation is an integral part of the body's physiological repair mechanism, unless it remains unresolved and becomes pathological, as evident in the progressive nature of neurodegeneration. Based ...on studies from outside the central nervous system (CNS), it is now understood that the resolution of inflammation is an active process, which is dependent on well‐orchestrated innate and adaptive immune responses. Due to the immunologically privileged status of the CNS, such resolution mechanism has been mostly ignored. Here, we discuss resolution of neuroinflammation as a process that depends on a network of immune cells operating in a tightly regulated sequence, involving the brain's choroid plexus (CP), a unique neuro‐immunological interface, positioned to integrate signals it receives from the CNS parenchyma with signals coming from circulating immune cells, and to function as an on‐alert gate for selective recruitment of inflammation‐resolving leukocytes to the inflamed CNS parenchyma. Finally, we propose that functional dysregulation of the CP reflects a common underlying mechanism in the pathophysiology of neurodegenerative diseases, and can thus serve as a potential novel target for therapy.
Michal Schwartz and Kuti Baruch review the immunological processes involved in neuroinflammation and neurodegeneration, and how inflammation‐resolving cells are recruited to the CNS.
A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body’s intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect ...the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs). Combining data from transcriptional analysis of DAM at single-cell level and from human genome-wide association studies (GWASs), we discuss potential function of different DAM pathways in the diseased brain and outline how manipulating DAM may create new therapeutic opportunities.
Recent analyses of CNS immune cells in neurodegenerative conditions have identified a subset of microglia showing a unique transcriptional and functional signature, disease-associated microglia (DAM). This perspective proposes a role for DAM as a sensor of early CNS damage and discusses the therapeutic potential of modulating DAM function in CNS diseases.
Philosophers defined the eye as a window to the soul long before scientists addressed this cliché to determine its scientific basis and clinical relevance. Anatomically and developmentally, the ...retina is known as an extension of the CNS; it consists of retinal ganglion cells, the axons of which form the optic nerve, whose fibres are, in effect, CNS axons. The eye has unique physical structures and a local array of surface molecules and cytokines, and is host to specialized immune responses similar to those in the brain and spinal cord. Several well-defined neurodegenerative conditions that affect the brain and spinal cord have manifestations in the eye, and ocular symptoms often precede conventional diagnosis of such CNS disorders. Furthermore, various eye-specific pathologies share characteristics of other CNS pathologies. In this Review, we summarize data that support examination of the eye as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS. Translation of eye research to CNS disease, and deciphering the role of immune cells in these two systems, could improve our understanding and, potentially, the treatment of neurodegenerative disorders.
An interaction network exists among cells within the brain, maintaining brain homeostasis and ensuring its functional plasticity. In addition to neurons, participating cells include astrocytes, ...oligodendrocytes, and microglia. Peripheral immune cells, such as monocytes and lymphocytes, have also been found to play an important role in supporting the brain in health and assisting in its repair. Here, we describe the multiple immune-specific modes of cellular dialogue among cells within the mammalian brain and their crosstalk with the periphery in both health and disease. We further suggest that interventions directed at boosting the peripheral immune response can restore the balance between the brain and the immune system and can rewire their communication to modify chronic neurodegenerative diseases.
Astrocytes and oligodendrocytes can act as immunocompetent cells under pathological conditions.A bidirectional relationship exists between non-neuronal cells and resident microglia in health and disease.Monocyte-derived macrophages display activities within the mammalian brain that are not performed by microglia.Immune checkpoint blockade immunotherapy in mouse models of Alzheimer’s disease can rewire the dialogue between multiple non-neuronal cell types within the brain, offering promising avenues for future therapeutic research.
Since the studies of Medawar and Burnet some 70 years ago, it was widely accepted that the CNS cannot tolerate any immune activity, under any circumstances. Over the past two decades, my team ...initiated a reversal of this dogma, by demonstrating that the brain requires support from innate and adaptive immune cells for its maintenance and repair. Deep understanding of these relationships by our team and by others led us to propose that the immune cells that are hosted within the brain's borders, together with neurons and non-neuronal cells, form an ecosystem that enhances the resilience of the brain and its robustness in withstanding continuous and diverse perturbations. Accordingly, any dysfunction in this brain-immune communication might impact brain activity. As aging is the major risk factor in dementia including Alzheimer's disease, we propose that dysfunction of any aspect of the brain-immune ecosystem could affect disease onset and severity, but may be amenable to immune intervention. This model led us to propose that defeating such diseases might be accomplished by harnessing the immune system, which is either exhausted or insufficient. We found that rejuvenating the immune system by transiently blocking the inhibitory PD-1/PD-L1 immune checkpoint pathway, initiates an immune response in the periphery that leads to disease modification within the brain by reducing multiple parameters that contribute to disease escalation, including neural loss, local inflammation, and phospho- and aggregated-tau in tauopathy, and soluble oligomers of amyloid beta in amyloidosis. In this lecture, we will focus on the choroid plexus-immune-brain axis as a gateway for leukocyte homing to the brain and as a site that remotely affects the brain's fate, via the CSF. Together, our studies show that targeting the immune system provides new avenues for understanding and treating neurodegenerative diseases.
For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or ...to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases. Moreover, it is now understood that the barriers of the brain are not uniform in their interactions with the circulating immune cells. The implications of these new findings to the basic understanding of CNS repair processes, brain aging, and a wide spectrum of CNS disorders, including acute injuries, Rett syndrome, Alzheimer's disease, and multiple sclerosis, will be discussed.
The poor recovery of the central nervous system (CNS) after injury, coupled with its complex and immunologically-privileged nature, led to the belief that CNS repair is different from the repair of ...other tissues. Here, we consider CNS repair from a novel perspective, suggesting that CNS responses to injury resemble wound healing. Extrapolating the classical wound healing model suggests that poor CNS recovery is an outcome of insufficient resolution of interim reparative events that precede tissue regeneration and renewal, a state reminiscent of chronic/unresolved wounds. This comparison requires reevaluation of the inflammatory response, glial scarring, and barrier permeability, traditionally considered obstacles to CNS repair. Understanding the similarity to wound healing suggests new research directions and therapeutic avenues for CNS injuries.
Inadequate axonal regeneration is a common phenomenon occurring following acute injury to the central nervous system (CNS), and is often associated with permanent neurological deficits. The injured ...axons attempting to regenerate face the inhospitable environment of the CNS scar, which can hinder axonal growth and sprouting. In addition, in response to the insult, intense activation and infiltration of immune cells take place. Both the scar tissue and immune response, which have received a bad reputation in the context of CNS repair are essential for the overall recovery from CNS injuries, but are not optimally controlled. The glial scar contributes to protection of the spared neural tissues by establishing a boundary between damaged and salvageable tissue, and by educating the immune cells to promote the healing of the CNS tissue. In turn, the immune cells, and in particular the infiltrating macrophages, exert several functions at the lesion site, including resolution of the microglial response, control of scar tissue degradation, and production of growth factors; thereby, promoting neuronal survival, axonal regeneration, and tissue remodeling. As axonal regeneration and tissue remodeling are viewed as critical steps for the overall functional recovery following CNS injury, a detailed understanding of the mechanisms underlying the timely formation and degradation of the CNS scar, and its crosstalk with the inflammatory response, are of great importance, both biologically and clinically. GLIA 2014;62:1895–1904
Main Points:
Infiltrating macrophages are critical for resolution of inflammation, scar degradation and CNS tissue remodeling.
The glial scar is a time-dependent protective barrier and immunoregulatory scaffold.
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