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Biomarkers of Neuroinflammation: Proceedings of a Workshop (2018)

Chapter: 3 State of the Science of Neuroinflammation in Central Nervous System Disorders

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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
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3

State of the Science of Neuroinflammation in Central Nervous System Disorders

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×

Neuroinflammation is similar to peripheral inflammation in many respects and in at least some prototypical neuroinflammatory diseases, such as MS, in which similar types of immune cells are sequestered into regions of damage, said Brian Campbell. He described inflammation as a response by the immune system to either segregate or remove a damaging stimulus in order to help facilitate the healing process by increasing blood vessel permeability, recruiting immune cells into the area, and releasing inflammatory mediators, such as cytokines and chemokines. In the CNS, the resident immune cells are microglia, which can be detected via positron emission tomography (PET) imaging with ligands that bind to the TSPO, also known as the peripheral benzodiazepine receptor (PBR). In MS, elevated TSPO binding is seen in both the acute and chronic inflammatory states (Ciccarelli et al., 2014) and is also seen in other CNS diseases such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and stroke, diseases that Campbell noted are not classically considered neuroinflammatory conditions. However, Gary Landreth commented that neuroinflammation is an invariant feature of neurodegenerative disease. Despite the fact that there are hundreds of publications linking TSPO to neuroinflammatory disease, Campbell said there is more to neuroinflammation than microglia, and Robert Innis said much remains unknown about microglial biology.

MICROGLIA AND NEUROINFLAMMATION

Microglia comprise approximately 10 percent of cells in the brain, said Campbell. They derive exclusively from yolk sac progenitors, not from bone marrow or other hematopoietic stem cells, and enter the brain very early in development, according to Beth Stevens. Landreth added that all microglia derive from cell proliferation and self-renewal of these progenitors, but said that the biology around these progenitors and the natural history of microglia, including metabolic changes, have been poorly explored. Similar to the way peripheral immune cells function, microglia defend against damage by continuously surveilling the brain for perturbations. But Campbell said they also modulate neural systems and circuits, provide trophic support, and cause synapse pruning (see Figure 3-1). Indeed, he said that the basic function of microglia is homeostasis. Stevens noted that microglia appear to undergo dramatic changes in the context of normal aging, increasing classic immune responses, but decreasing some of their homeostatic sensing functions. She said they also

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
Image
FIGURE 3-1 Microglia serve multiple functions in the brain, including synaptic pruning, phagocytosis, and the secretion of growth factors to maintain homeostasis. When activated they may become neurotoxic or reparative.
NOTE: ATP = adenosine triphosphate; ECM = extracellular matrix; ROS = reactive oxygen species; TLR = toll-like receptor.
SOURCE: Presentation by Campbell, March 20, 2017.

interact with astrocytes, although the relationship between these two cell types and the effect on neuroinflammatory disease is not well understood. Landreth noted that in addition to resident microglia, an inflammatory subset of blood-borne monocytes infiltrates the brain in a number of CNS disorders, and then acquires microglia markers and produces inflammatory cytokines within 72 hours that make them indistinguishable from resident microglia (Sieweke and Allen, 2013).

Understanding the biology of neuroinflammation was advanced through studies of the rare, progressive neurodegenerative Nasu-Hakola disease (also known as PLOSL), which arises from mutations in the TREM2 gene (Bianchin et al., 2004), said Landreth. TREM2 is only expressed in myeloid cells (i.e., microglia in the brain), indicating that these cells are sufficient to drive neurodegeneration all by themselves, he said. Moreover, many genome-wide association studies (GWASs) have identified variants of TREM2 that increase the risk of AD and other neurodegenerative diseases. One variant in particular, R47H, is sufficient to

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×

increase the risk of AD threefold, an effect size similar to that observed for ApoEε4, said Landreth (Guerreiro et al., 2013).

In AD, the TREM2-positive inflammatory cells surrounding plaques have been shown to be peripherally derived monocytes rather than resident microglia, and knocking out TREM2 in AD mouse models largely abrogates the accumulation of inflammatory cells around the plaques in an age- and disease-progression‒dependent fashion (Jay et al., 2015). Yet, while TREM2 has become the focus of research on neuroinflammation, Landreth said there remains a poor understanding of the biology, including the differential biology of the resident microglia and infiltrating monocytes over the course of the disease, and the consequences of different mutations.

TREM2 also appears to affect neuroinflammation through soluble extracellular fragments shed through cleavage of the cell-surface receptor. A recent paper showed that these cleavage products interact with microglia to drive a strong proinflammatory response (Zhong et al., 2017). In addition, elevations of soluble TREM2 in the cerebrospinal fluid have been shown to correlate with the deposition of amyloid in patients with dominantly inherited forms of AD (Suarez-Calvet et al., 2016), suggesting that soluble forms of TREM2 may represent a valuable biomarker for disease, said Landreth.

While the TSPO and TREM2 research supports the view that microglial activation is important in nearly all CNS disorders, Campbell noted that an operational definition of microglial activation is still needed. He said that when stimulated, microglia enter a responding stage with a number of different phenotypes that may alternatively internalize toxic substances, take on a migratory phenotype, release proinflammatory cytokines or reactive oxygen species, or release factors involved in repairing, such as neuroprotective or angiogenic factors, anti-inflammatory cytokines, prostaglandins, microvesicles, and microRNAs or miRNAs (Loane and Byrnes, 2010). Biomarkers to identify these different phenotypes could advance understanding about not just what causes microglia to become activated but also the consequences of that activation, said Campbell. They could also help define the temporal correlation between different activation states of microglia in different diseases and patient populations, he said. Fiona Crawford concurred, noting that microglia are very fluid, changing their presentation depending on the context and the other cells they are interacting with at any given moment. Mouse models could prove very useful in understanding microglial activation profiles that reflect biological processes in vulnerable versus non-vulnerable re-

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×

gions of the brain, added Stevens. For example, her lab has shown in both HD and AD mouse models that changes in microglia markers in early stages of disease are very different from those seen once inflammation begins.

Landreth mentioned work by Joseph El Khoury and colleagues in which they identified a “microglial sensome,” a panel of microglial-specific genes that may be up- or downregulated in aging and various CNS diseases, and thus may be useful in identifying biomarkers (Hickman et al., 2013). Amit Bar-Or added that the complex nature of microglial biology and the lack of clarity about whether changes from normal are harmful or beneficial has stymied efforts to develop useful biomarkers.

SYNAPTIC PRUNING

As mentioned earlier, microglial function goes beyond neuroinflammation. Microglia also sculpt and prune neural circuits during normal development. This process is highly regulated and not random with respect to when and which synapses are removed, and the fact that this is developmentally regulated suggests that there must be both “on” and “off” signals, said Stevens. Moreover, synaptic pruning is necessary for precise synaptic connectivity and brain wiring, she said. The normal pruning process becomes aberrantly regulated in a host of different neurological diseases, contributing to synapse loss and dysfunction, said Stevens, adding that defects in pruning or remodeling may underlie neurological, neurodevelopmental, and neuropsychiatric disorders, including schizophrenia and autism, as well as in diseases of aging, such as AD. Synapse loss in AD appears to occur at an early stage of the disease, before overt inflammation, and is correlated to cognitive dysfunction. This correlation is even stronger than the correlation between cognitive dysfunction and plaques and tangle pathology, said Stevens.

Stevens commented on whether there could be a common mechanism in these diverse diseases that tells microglia which synapses to prune. Specific synapses and circuits are known to be vulnerable in various diseases, she said, which could mean there are mechanisms regulating the recognition process that might be relevant in the context of these diseases. For example, she noted that while synapses with less active inputs tend to be selectively eliminated, how they signal microglia about differences in neuronal activity is not well understood. Stevens suggested

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×

that identifying these signals could yield therapeutic targets and/or biomarkers. Signals that appear important in this process are associated with the complement cascade, in particular C1q and a downstream component, C3, she said. She added that while the complement cascade is best understood in the context of immunity and the process of clearing pathogens from cells, complement components may similarly tag and clear less active synapses. Her lab and others are just beginning to tease out the steps, proteins, receptors, and protective signals involved in this process.

There is also evidence that the control mechanisms in this system may be lost in disease states, she said. For example, genetic evidence from Steve McCarroll’s lab and others suggests that a particular form of C4 increases the risk of schizophrenia, possibly from overpruning of certain circuits. In neurodegenerative disease, pathways that normally are turned off may be turned back on again, suggesting a possible treatment target, said Stevens.

BLOOD‒BRAIN BARRIER DYSFUNCTION

The “blood‒brain barrier” is a term used to describe unique properties of the CNS vasculature that prevent molecules and ions from going from the blood into the brain, according to Richard Daneman. It is critical to maintain brain homeostasis and to protect the CNS from toxins, pathogens, and even the body’s own immune system; its importance is highlighted by diseases in which it is compromised, such as in stroke, brain trauma, epilepsy, and MS, said Daneman.

Most of the properties of the BBB are manifested within the endothelial cells that make up the walls of the blood vessels. Daneman described multiple differences among endothelial cells in the CNS compared to those in other tissues. First, CNS endothelial cells are held together by tight junctions. They also undergo extremely low rates of transcytosis or vesicle-mediated trafficking, and express proteins that pump out small lipophilic molecules that have gotten into the brain and selectively transport specific metabolites into the brain. Finally, they express low levels of molecules that in other tissues are responsible for binding immune cells to facilitate their entry into those tissues. All of these properties may be lost in the presence of neurological disease, said Daneman. He added that work done in the 1980s showed that these properties are not intrinsic to endothelial cells, but are induced by the CNS microenvi-

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×

ronment. Understanding how the BBB breaks down in different diseases could lead to the identification of both biomarkers and treatment targets, he said.

Daneman’s lab has studied the BBB in four disease models: stroke, MS, TBI, and epilepsy, each of which has a mouse model on which to conduct experimental studies. All of these diseases show massive BBB dysfunction at the site of the injury or lesion in both human and mouse models, he said. Yet while each has a different trigger—hypoxia/ischemia in stroke, inflammation in MS, trauma in TBI, and neural activity in epilepsy—Daneman and colleagues showed that the pattern of gene expression is similar over multiple time points corresponding to acute, subacute, and chronic responses. This allowed the researchers to identify a BBB dysfunction module—197 genes that are upregulated in at least three of the diseases, suggesting there may be a common pathway for BBB dysfunction. Daneman’s team went on to classify these genes into three groups with different temporal patterns. One group peaks early in the disease and then goes down at later time points, while a second group peaks at the subacute time point when there is the most BBB dysfunction. The third group often peaks at the subacute time point, but in some diseases it persists on the blood vessels into the chronic phase for well over 1 month after the initial insult. Interestingly these 197 genes are normally expressed at low levels in brain endothelial cells, but at high levels in leakier peripheral endothelial cells of the heart, kidney, and lung, suggesting a mechanism for breach of the BBB, said Daneman.

The other cells that are important in BBB function are the pericytes, which sit outside the vessels. Earlier work by Daneman and colleagues showed that the BBB is leakier when there are fewer pericytes (Daneman et al., 2010). Moreover, pericyte-deficient mice showed an upregulation of 145 peripheral endothelial genes, but only 1 of 400 BBB-specific genes, suggesting that pericytes inhibit the expression of these leaky genes. These observations led Daneman to hypothesize that upregulation of peripheral endothelial genes leads to BBB disruption during disease, at least in part because of a loss of endothelial–pericyte interactions. A screen in his lab for candidate genes that disrupt cellular barriers led to the identification of a family of genes (the EHD family) that regulate endocytosis and vesicle trafficking, said Daneman. One member of this family—EHD4—is upregulated in stroke and MS animal models, that is, conditions associated with BBB dysfunction, he said. Moreover, his lab showed that mice engineered to express high levels of EHD4 also

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×

showed BBB dysfunction, including fibrinogen leakage. Taken together, these studies suggest there is a common molecular pathway across many different neurological diseases for BBB dysfunction, which is characterized by loss of endothelial–pericyte interactions, upregulation of endothelial genes, increased vesicle trafficking and disruption of tight junctions, and leakage through the pericellular barrier, said Daneman. Development of endothelial biomarkers could be used to identify the location of damage to the BBB as well as the location of past damage, he said, adding that there may also be the potential to use these molecules as guide posts for targeted delivery of therapeutics. Daneman’s group is also working to identify serum biomarkers of BBB dysfunction by inducing breakdown of the BBB in an animal model and then analyzing serum with proteomic and metabolomic technologies.

Daneman noted that there are other possible mechanisms for moving cells and antibodies into the CNS, for example, different types of endothelial cells in the meningeal or choroid plexus vessels, antibody transporters at the BBB, the glymphatic system, and the meningeal lymphatic system. Edward Bullmore added that not all parts of the BBB are equally impermeable and that there may be active transport mechanisms for some immune modulators, such as interleukin 6 (IL-6).

FIBRINOGEN AND THE NEUROVASCULAR INTERFACE

Katerina Akassoglou has been studying the consequences of BBB disruption in diseases such as MS, stroke, and brain trauma, and classic neurodegenerative conditions, such as AD. Epidemiological studies show that increased leakage of plasma proteins from inside the vessels to the surrounding tissue correlates with worsening pathology and worse prognosis, she said. Her lab aims to identify the peripheral triggers and molecular determinants of this pathological process, which could lead not only to the development of new imaging tools to image the neurovascular interface but also to new therapeutics, animal models, and biomarkers. In particular, they focus on fibrinogen, a protein that is abundantly deposited in human neurological diseases as well as in animal models; that plays dual functions in both blood coagulation and inflammation; and that represents a druggable interaction.

Fibrinogen is a non-pathogenic soluble protein in the blood, but with the action of thrombin, it forms insoluble fibrin that binds to platelets to form clots and is highly proinflammatory, said Akassoglou. She and oth-

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×

ers have shown that fibrin is required for the development of many CNS diseases, including MS (Adams et al., 2007; Davalos et al., 2012), brain trauma (Schachtrup et al., 2010), and AD (Cortes-Canteli et al., 2010). Akassoglou and her colleagues hypothesized that two non-overlapping epitopes in the fibrinogen molecule mediate coagulation and inflammation, and wondered if these two activities could be disassociated either genetically or pharmacologically to target the damaging function in inflammation without affecting beneficial effects in hemostasis. What they found is that microglia are the main cell targets of fibrin in the CNS through the binding of one of these epitopes to the microglia CD11b/CD18 integrin receptor (complement receptor 3), while another epitope in the fibrin molecule binds to platelets to cause coagulation (Adams et al., 2007). Akassoglou said fibrinogen is specific among plasma proteins to induce microglia activation (Davalos et al., 2012). Fibrinogen induces demyelination and recruits macrophages and T cells (Ryu et al., 2015), she said, and blocking the interaction of fibrin and the CD11b receptor was shown in mouse models to suppress innate immunity and the downstream effects of neurodegeneration (Adams et al., 2007; Davalos et al., 2012). As described in Chapter 5, Akassoglou and colleagues are developing molecular probes to be used with magnetic resonance imaging to monitor coagulation activity in neuroinflammatory disease.

Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×

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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
Page 23
Suggested Citation:"3 State of the Science of Neuroinflammation in Central Nervous System Disorders." National Academies of Sciences, Engineering, and Medicine. 2018. Biomarkers of Neuroinflammation: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24854.
×
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Neuroinflammation is a burgeoning area of interest in academia and biopharma, with a broadly acknowledged role in many central nervous system (CNS) disorders. However, there is little agreement on the pathophysiological mechanisms that underlie the manifestations of neuroinflammation in the CNS compartment and how neuroinflammation operates as a driver and also as a consequence of disease in the brain. Moreover, another unclear area is how to translate increased understanding of the mechanisms that underlie neuroinflammation and its manifestations in the CNS to therapeutics.

To address these gaps in understanding mechanisms and how to translate that understanding into therapeutics, the Forum on Neuroscience and Nervous System Disorders of the National Academies of Sciences, Engineering, and Medicine convened a workshop on March 20-21, 2017, bringing together key leaders in the field from industry, academia, and governmental agencies to explore the role and mechanisms of neuroinflammation in a variety of CNS diseases. The workshop also considered strategies to advance the identification and validation of biomarkers of neuroinflammation that could accelerate development of therapies, bringing much-needed treatments to patients with disorders ranging from neuroinflammatory diseases such as multiple sclerosis (MS) to neuropsychiatric disorders such as depression. This publication summarizes the presentations and discussions from the workshop.

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