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Physiology of Chronic Neuroinflammation
Neuroinflammation has come to stand for chronic, central nervous system 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 there is an increase in gene expression. This leads to the production of numerous potentially neurotoxic mediators. These mediators are important in the normal functions of microglia and their production is decreased once the task is complete. In chronic neuroinflammation microglia remain activated for an extended period and may contribute to neuronal death through the actions of their mediators.

Unique features characterize Neuroinflammation but the essential characteristics of inflammation in other organs are similar. One main similarity is the localized production of chemoattractant molecules at the sites of inflammation. The following list contains a few of the numerous substances are secreted when microglia are activated:

Cytokines
Microglia activate the proinflammatory cytokines interleukin (IL)-1α, IL-1b and TNF-α in the CNS. Direct injection of the cytokines IL-1α, IL-1β and TNF-α into the CNS result in local inflammatory responses and neuronal degradation. Cytokines play a potential role in neurodegeneration when microglia remain in a sustained activated state. 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: XCL, CCL, CXCL, and CX3CL. Microglial cells are sources of some chemokines and express the monocyte chemoattractant protein-1 (MCP-1) chemokine in particular. Other inflammatory cytokines like IL-Iβ, 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 (cathepsin B has been found to be increased in both Alzheimer’s disease and MS), the matrix metalloproteinases MMP-1, MMP-2, MMP-3, and MMP-9 (MMP-1 and MMP-3 are significantly elevated in AD), the metalloprotease-disintegrin ADAM8, plasminogen which forms outside microglia and degrades the extracellular matrix. Elastase, another protease, could have large negative effects on the extracellular matrix.

Amyloid Precursor Protein
Plaques in Alzheimer’s disease contain activated microglia. Amyloid plaques can stimulate microglia to produce neurotoxic compounds such as cytokines, excitotoxin, nitrite oxide and lipophylic amines all, which cause neural damage. These plaques result from abnormal proteolytic cleavage of membrane bound amyloid precursor protein (APP), microglia synthesize APP in response to excitotoxic injury. 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 b 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, parenchymal microglia undergo mitosis and bone marrow derived progenitor cells migrate into the parenchyma via the meninges and vasculature. 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.

Accumulation of minor neuronal damage, the ‘wear and tear’ or 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 be another factor contributing to age-associated microglial activation. Another factor might be the accumulation of advanced glycation end products, which accumulate with aging. These proteins are strongly resistant to proteolytic processes and promote protein cross-linking.

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.” Here are some prominent examples of microglial cell’s role in neurodegenerative disorders.

Alzheimer’s Disease
Alzheimer’s Disease 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 though 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
Nonsteroidal 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, 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 upregulated 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 PD or DLB, activated microglia leading to enhanced dopaminergic neurotoxicitiy.”

Human Immunodeficiency Virus
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.

Infected microglia contain viral particles intracellularly. The number of activated microglia in the CNS better correlate with HAD than the presence and amount of HIV-1 infected cells and microglial activation is a better correlate of neuronal damage than HIV-1 infection in the CNS.

“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.”

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, and when activated by HIV-1 or viral proteins, they secrete or induce other cells to secrete neurotoxic factors; this process is accompanies 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 “activate 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. Primarily localized to the subarachnoid space while cytokines and chemokines are produced inside the blood brain barrier. The inflammatory response, triggered by glia, may cause intracerebral edema.

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 proliferation. 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.

Inhibit Microglia Activation
One way to control neuroinflammation is to inhibit microglial activation. Studies on microglia have shown that microglia are activated by diverse stimuli but they are dependent on activation of mitogen-activated protein kinase (MAPK). Previous approaches to downregulate activated microglia focused on immunosuppressants. Recently, minocycline (a tetracycline derivative) has shown downregulation of microglial MAPK. Another promising treatment is CPI-1189 which is a proapoptotic cytokine tumor necrosis factor (TNF) α-inhibiting compound that also downregulates MAPK.

Chemokine Receptor
The chemokine receptor, CX3CR1, is expressed by microglia in the central nervous system. Fractalkine (CX3CL1) is the exclusive ligand for the 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 include the enzymes responsible for the production of extracellular amyloid such as β-secretase and γ-secretase inhibitors. Currently the γ-secreatase 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) potent anti-inflammatory steroids inhibit both central and peripheral cytokine synthesis and action.