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Physiology of chronic neuroinflammation

The word neuroinflammation has come to stand for chronic, central nervous system (CNS) specific, inflammation-like glial responses that may produce neurodegenerative symptoms such as plaque formation, dystrophic neurite growth, and excessive tau phosphorylation. It is important to distinguish between acute and chronic neuroinflammation. Acute neuroinflammation is generally caused by some neuronal injury after which microglia migrate to the injured site engulfing dead cells and debris. The term neuroinflammation generally refers to more chronic, sustained injury when the responses of microglial cells contribute to and expand the neurodestructive effects, worsening the disease process.

When microglia are activated they take on an amoeboid shape and they increase their gene expression. Increased gene expression leads to the production of numerous potentially neurotoxic mediators. These mediators are important in the normal functions of microglia and their production is usually decreased once their task is complete. In chronic neuroinflammation, microglia remain activated for an extended period during which the production of mediators is sustained longer than usual. This increase in mediators contributes to neuronal death.

Neuroinflammation is unique from inflammation in other organs, but does include some similar mechanisms such as the localized production of chemoattractant molecules to the site of inflammation. The following list contains a few of the numerous substances that are secreted when microglia are activated:

Cytokines

Microglia activate the proinflammatory cytokines IL-1α, IL-1β and TNF-α in the CNS. Cytokines play a potential role in neurodegeneration when microglia remain in a sustained activated state. Direct injection of the cytokines IL-1α, IL-1β and TNF-α into the CNS result in local inflammatory responses and neuronal degradation. This is in contrast with the potential neurotrophic (inducing growth of neurons) actions of these cytokines during acute neuroinflammation.

Chemokines

Chemokines are cytokines that stimulate directional migration of inflammatory cells in vitro and in vivo. Chemokines are divided into four main subfamilies: C, CC, CXC, and CX₃C. Microglial cells are sources of some chemokines and express the monocyte chemoattractant protein-1 (MCP-1) chemokine in particular. Other inflammatory cytokines like IL-1β, TNF-α and lipopolysaccharide (LPS) may stimulate microglia to produce MCP-1, MIP-1α, and MIP-1β. Microglia can express CCR3, CCR5, CXCR4, and CX3CR1 in vitro. Chemokines are proinflammatory and therefore contribute to the neuroinflammation process.

Proteases

When microglia are activated they induce the synthesis and secretion of proteolytic enzymes that are potentially involved in many functions. There are a number of proteases that posses the potential to degrade both the extracellular matrix and neuronal cells that are in the neighborhood of the microglia releasing these compounds. These proteases include; cathepsins B, L, and S, the matrix metalloproteinases MMP-1, MMP-2, MMP-3, and MMP-9, and the metalloprotease-disintegrin ADAM8 plasminogen which forms outside microglia and degrades the extracellular matrix. Both Cathepsin B, MMP-1 and MMP-3 have been found to be increased in Alzheimer’s disease (AD) and cathepsin B is increased in multiple sclerosis (MS). Elastase, another protease, could have large negative effects on the extracellular matrix.

Amyloid precursor protein

Microglia synthesize amyloid precursor protein (APP) in response to excitotoxic injury. Plaques result from abnormal proteolytic cleavage of membrane bound APP. Amyloid plaques can stimulate microglia to produce neurotoxic compounds such as cytokines, excitotoxin, nitrite oxide and lipophylic amines, which all cause neural damage. Plaques in Alzheimer’s disease contain activated microglia. A study has shown that direct injection of amyloid into brain tissue activates microglia, which reduces the number of neurons. Microglia have also been suggested as a possible source of secreted β amyloid.

Aging of microglia

Microglia undergo a burst of mitotic activity during injury; this proliferation is followed by apoptosis to reduce the cell numbers back to baseline. Activation of microglia places a load on the anabolic and catabolic machinery of the cells causing activated microglia to die sooner than non-activated cells. To compensate for microglial loss over time, microglia undergo mitosis and bone marrow derived progenitor cells migrate into the brain via the meninges and vasculature.

Accumulation of minor neuronal damage that occurs during normal aging can transform microglia into enlarged and activated cells. These chronic, age-associated increases in microglial activation and IL-1 expression may contribute to increased risk of Alzheimer’s disease with advancing age through favoring neuritic plaque formation and susceptible patients. DNA damage might contribute to age-associated microglial activation. Another factor might be the accumulation of advanced glycation endproducts, which accumulate with aging. These proteins are strongly resistant to proteolytic processes and promote protein cross-linking.

Research has discovered dystrophic (defective development) human microglia. “These cells are characterized by abnormalities in their cytoplasmic structure, such as deramified, atrophic, fragmented or unusually tortuous processes, frequently bearing spheroidal or bulbous swellings.” The incidence of dystrophic microglia increases with aging. Microglial degeneration and death have been reported in research on Prion disease, Schizophrenia and Alzheimer’s disease, indicating that microglial deterioration might be involved in neurodegenerative diseases. A complication of this theory is the fact that it is difficult to distinguish between “activated” and “dystrophic” microglia in the human brain.

Neurodegeneration

Neurodegenerative disorders are characterized by progressive cell loss in specific neuronal populations. “Many of the normal trophic functions of glia may be lost or overwhelmed when the cells become chronically activated in progressive neurodegenerative disorders, for there is abundant evidence that in such disorders, activated glia play destructive roles by direct and indirect inflammatory attack.” The following are prominent examples of microglial cells' role in neurodegenerative disorders.

Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease where the brain develops abnormal clumps (amyloid plaques) and tangled fiber bundles (neurofibrillary tangles).

There are many activated microglia over-expressing IL-1 in the brains of Alzheimer patients that are distributed with both αβ plaques and neurofibrillary tangles. This over expression of IL-1 leads to excessive tau phosphorylation that is related to tangle development in Alzheimer’s disease.

Many activated microglia are found to be associated with amyloid deposits in the brains of Alzheimer’s patients. Microglia interact with β-amyloid plaques through cell surface receptors that are linked to tyrosine kinase based signaling cascades that induce inflammation. When microglia interact with the deposited fibrillar forms of β-amyloid it leads to the conversion of the microglia into an activated cell and results in the synthesis and secretion of cytokines and other proteins that are neurotoxic.

Treatment

Non-steroidal anti-inflammatory drugs (NSAIDs) have proven to be effective in reducing the risk of AD. "Sustained treatment with NSAIDs lowers the risk of AD by 55%, delays disease onset, attenuates symptomatic severity and slows the loss of cognitive abilities. The main cellular target for NSAIDs is thought to be microglia. This is supported by the fact that in patients taking NSAIDs the number of activated microglia is decreased by 65%."

Parkinson’s disease

Parkinson’s disease is a movement disorder in which the dopamine producing neurons in the brain, don’t work properly. The area of the brain affected by Parkinson’s is called the substantia nigra. It is here that the neurons either become impaired or die. The substantia nigra has one of the highest concentrations of microglia in the brain.

Activated microglial cells have been found around extraneuronal neuromelanin released from impaired dopaminergic neurons in the substantia nigra of patients with Parkinson’s disease. A study by Henrik Wilms discovered that neuromelanin acts as a chemoattractant for microglial cells and induces morphological transformation of microglia cells to an activated state. Neuromelanin also induces synthesis of proinflammatory microglial molecules. All of the inflammatory compounds that are up-regulated in Parkinson’s disease can be produced by microglia, especially activated microglia.

Another study conducted by Wei Zhang stated, “…We have shown for the first time aggregated α-synuclein, the major components of Lewy bodies in patients with Parkinson's disease or dementia with Lewy bodies, activated microglia leading to enhanced dopaminergic neurotoxicitiy.”

Microglia and viruses

Human Immunodeficiency Virus (HIV)

The infection of mononuclear phagocytes with HIV-1 is an important element in the development of HIV-associated dementia complex (HAD). The only brain cell type that is “productively” infected with the virus are microglial cells. It has also become clear that neurotoxic mediators released from brain microglia play an important role in the pathogenesis of HIV-1.

“HIV-1 can enter the microglial cell via CD4 receptors and chemokine co-receptors such as CCR3, CCR5, and CXCR4, with CCR5 being the most important of these. Interestingly, humans with double allelic loss of CCR5 are virtually immune to HIV. IL-4 and IL-10 enhance the entry and replication of HIV-1 in microglia through the up-regulation of CD4 and CCR5 expression, respectively. The chemokines CCL5/RANTES, CCL3/MIP-1α, CCL4/MIP-1β, all of which bind to CCR5, are inhibitory to HIV-1 replication in microglial cells, apparently by their ability to block viral entry.”

Infected microglia contain viral particles intracellularly. There is a correlation between the severity of dementia and microglial production of neurotoxins.

One discrepancy in HAD is the limited number of HIV-1 infected microglia in comparison to the many CNS abnormalities that occur. This suggests that chemical factors that are released from microglial cells are contributing to neuronal loss. “It has become more and more apparent that HIV-1 infected microglial cells actively secrete both endogenous neurotoxins such as TNF-α, IL-1β, CXCL8/IL-8, glutamate, quinolinic acid, platelet activating factor, eicosanoids, and NO as well as the neurotoxic viral proteins Tat, gp120, and gp41.”

Microglia are the main target of HIV-1 in the brain. When activated by HIV-1 or viral proteins, they secrete or induce other cells to secrete neurotoxic factors; this process is accompanied by neuronal dysfunction (HAD).

Herpes simplex virus

Herpes simplex virus (HSV) can cause herpes encephalitis in babies and immunocompetent adults. Studies have shown that long-term neuroimmune activation persists after the herpes infection in patients. Microglia produce cytokines that are toxic to neurons; this may be a mechanism underlying HSV-related CNS damage. It has been found that “active microglial cells in HSV encephalitis patients do persist for more than 12 months after antiviral treatment.”

Microglia and bacteria

Lipopolysaccharide (LPS) is the major component of the outer membrane of a gram-negative bacterial cell wall. LPS has been shown to activate microglia in vitro and stimulates microglia to produce cytokines, chemokines, and prostaglandins. “Although LPS has been used as a classic activating agent, a recent study of rat microglia demonstrated that prolonged LPS exposure induces a distinctly different activated state from that in microglia acutely exposed to LPS.”

Streptococcus pneumoniae

Streptococcus pneumoniae is the most common cause of bacterial meningitis. It is primarily localized to the subarachnoid space while cytokines and chemokines are produced inside the blood brain barrier. Microglia interact with streptococcus via their TLR2 receptor; this interaction then activates microglia to produce nitric oxide which is neurotoxic. The inflammatory response, triggered by microglia, may cause intracerebral edema.

Microglia and parasites

Plasmodium falciparum

Plasmodium falciparum is a parasite that causes malaria in humans. A serious complication of malaria is cerebral malaria (CM). CM occurs when red blood cells break through the blood brain barrier causing microhemorrhages, ischemia and glial cell growth. This can lead to microglial aggregates called Durck’s granulomas. Recent research has indicated that microglia play a major role in the pathogenesis of CM.

Current attempts to control neuroinflammation

Inhibit microglia activation

One way to control neuroinflammation is to inhibit microglial activation. Studies on microglia have shown that they are activated by diverse stimuli but they are dependent on activation of mitogen-activated protein kinase (MAPK). Previous approaches to down-regulate activated microglia focused on immunosuppressants. Recently, minocycline (a tetracycline derivative) has shown down-regulation of microglial MAPK. Another promising treatment is CPI-1189, which induces cell death in a TNF α-inhibiting compound that also down-regulates MAPK.

Regulate chemokine receptor

The chemokine receptor, CX3CR1, is expressed by microglia in the central nervous system. Fractalkine (CX3CL1) is the exclusive ligand for CX3CR1 and is made as a transmembrane glycoprotein from which a chemokine can be released. Cardona, et al. stated in 2006 that “using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity.” Further studies into how CX3CR1 regulates microglial neurotoxicity could lead to new therapeutic strategies for neuroprotection.

Inhibit amyloid deposition

Inhibitors of amyloid deposition include the enzymes responsible for the production of extracellular amyloid such as β-secretase and γ-secretase inhibitors. Currently the γ-secretase inhibitors are in phase II clinical trials as a treatment for Alzheimer’s disease but they have immunosuppressive properties, which could limit their use. Another strategy involves increasing the antibodies against a fragment of amyloid. This treatment is also in phase II clinical trials for the treatment of Alzheimer’s disease.

Inhibit cytokine synthesis

Glucocorticosteroids (GCS) are anti-inflammatory steroids that inhibit both central and peripheral cytokine synthesis and action. In a study conducted by Kalipada Pahan from the Department of Pediatrics at the Medical University of South Carolina, both lovastatin and sodium phenylacetate were found to inhibit TNF-α, IL-1β, and IL-6 in rat microglia. This shows that the mevalonate pathway plays a role in controlling the expression of cytokines in microglia and may be important in developing drugs to treat neurodegenerative diseases.