Neuroinflammation Proteins

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Neuroinflammation Proteins

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Neuroinflammation Proteins Background

Neuroinflammation refers to an immune response in the central nervous system (CNS) and is important for protecting neurons from threats, but chronic, uncontrolled neuroinflammation can be detrimental to normal neuronal function. Many normal neuronal functions are orchestrated by increases of intracellular calcium, which regulate synaptic plasticity and other important processes. Similar to neuroinflammation, chronic, uncontrolled increases in intracellular calcium (Ca2+) levels can be detrimental to normal neuronal function.


Microglia and neuroinflammation

Neuroinflammation is a normal process that occurs in the CNS in response to disease and injury. Neuroinflammation is distinct from peripheral inflammation in that it lacks features such as pain, heat, redness, and swelling that are characteristic of peripheral inflammation. Additionally, the CNS was long thought of as immune privileged due to lack of allograft rejection, as well as its lack of lymphatic drainage, the presence of the blood-brain barrier (BBB), and the relatively low expression of antigen presentation molecules such as major histocompatibility complexes I and II (MHC-I and MHC-II). Today, the CNS is known to carry out an innate immune response that is distinct from the peripheral innate immune response. In general, neuroinflammation refers to glial activation in the CNS. One of the primary effector cells of neuroinflammation are microglia, the resident macrophages of the CNS.

Microglia are derived from primitive myeloid precursor cells from yolk sac that migrate to and become trapped in the CNS early in development prior to the onset of blood circulation. Unlike peripheral macrophages, microglia are not renewed from bone marrow hematopoetic stem cells, suggesting that microglia are distinct from peripheral macrophages as well as long-lived and/or self-renewing. Microglia are numerous in the brain, making up 5-15% of cells. Previously, microglia were thought to simply function as support cells to neurons, but we now understand that microglia play an active role in development, plasticity, neurotransmission, and host defense. In the following section, I will discuss the various functional states of microglia and the various molecular mediators that are involved in maintenance of and transition between these states. For a review of these activation states and the conversion between them, refer to Figure 1.

Microglia have three main activation states

Fig. 1 Microglia have three main activation states.


Chronic neuroinflammation

Acutely activated microglia are often neuroprotective, in contrast, chronic, uncontrolled neuroinflammation may induce neurotoxicity. Acute microglia activation is important for eliminating pathogenic threats via the production of ROS, RNS, cytokine signaling, and phagocytosis. However, all three of these can cause direct harm to surrounding neurons.

ROS and RNS contribute to oxidative stress by interfering with normal mitochondria function. NO can inhibit cytochrome c oxidase by competing with oxygen, leading to decreased production of ATP, thus starving the cell of its primary energy source. Mitochondrial DNA is also more susceptible to oxidative damage than nuclear DNA. Disruptions of mitochondria function can eventually lead to cell death. In addition to damage to mitochondrial and nuclear DNA, ROS and RNS cause lipid and protein peroxidation. Oxidative stress can also interfere with the normal function of receptors important for Ca2+ regulation. Briefly, oxidative stress can increase the levels of extracellular glutamate by reducing activity and expression of excitatory amino acid transporters (EAATs) on astrocytes, which increases the opening of ligand-gated Ca2+ channels. Furthermore, oxidative stress can increase the function of ryanodine receptors (RyRs) via nitrosylation, which would increase Ca2+ flux out of the endoplasmic reticulum (ER), further contributing to Ca2+ dysregulation. Ca2+ dysregulation can lead to excitotoxic cell death. Cytokines released during chronic neuroinflammation can also lead to dysregulation of Ca2+ signaling by altering the activity of glutamate receptors and L-type voltage dependent Ca2+ channels.

Microglia can also trigger neuronal death directly via phagocytosis and cytokine signaling. Phagocytosis is useful for removing pathogens, infected cells, and harmful protein aggregates, but can also trigger apoptosis of viable but stressed neurons during times of chronic microglia activation. Microglia release TNFα, a cytokine that activates death domain receptors on neurons, which triggers caspase-3 cleavage and subsequent apoptosis. Neurons in the early stages of apoptosis express calreticulin, which interacts with its receptor on microglia, low-density lipoprotein receptor-related protein (LRP), triggering phagocytosis. Neuronal surface expression of phosphatidylserine also triggers their phagocytosis via interaction with the microglial vitronectin receptor. This is important for eliminating neurons infected with pathogens, but during chronic microglia activation these responses can lead to the destruction of healthy neurons. For example, neurons stressed with ROS upregulate phosphatidylserine but do not undergo apoptosis unless phagocytosed by activated microglia. ROS and RNS may play a larger role in neuroinflammation-mediated cell death than cytokine signaling pathways.

Chronic neuroinflammation is self-propagating via a variety of mechanisms. ROS and RNS can induce NFκB-mediated transcription and translation of pro-inflammatory cytokine genes and proteins, recruiting neighboring microglia to become activated which will in turn lead to the production of more cytokines, RNS, and ROS. Cytokines activate their receptors on microglia which lead to further production of cytokines via activation of transcription factors such as NFκB and STAT1 and 2. Other cells, such as astrocytes, can also respond to cytokines and contribute to neuroinflammation. Microglial initiation of neuronal cell death leads to the release of DAMPs, such as nucleotides and ATP, into the microenvironment leading to further microglia activation.

Functionally, chronic neuroinflammation is harmful to adaptive behaviors. Chronic neuroinflammation induced by chronic infusion of LPS induces memory deficits in hippocampal-dependent spatial memory tasks, including the Morris water maze (MWM) and spontaneous alternation in the T-maze Memory deficits induced by chronic LPS infusion worsen with longer infusion duration, demonstrating the time-dependent nature of neuroinflammatory deficits. Underlying the memory deficit observed during chronic LPS infusion are deficits in LTP. Additionally, chronic LPS infusion decreases synaptic markers. A background level of chronic neuroinflammation, such as that observed in aging, can increase depressive and sickness behaviors in mice following acute inflammation. Chronic microglia activation may also underlie depressive symptoms triggered by chronic stress.

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