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Acute and Chronic Inflammation: Microglia in Neuroprotection and Neurodegeneration

By: Chandra Mohan, Ph.D. MilliporeSigma, Temecula, CA

The term neurodegeneration characterizes a chronic loss of neuronal structure and function leading to progressive mental impairments. Generally, the inci­dence of neurodegeneration increases with age. However, infectious agents may also induce neuronal death via apoptosis. Years of research has linked neurodegeneration to the phenomenon of neuroinflammation, which could be caused by microvascular damage, atherosclerosis, age-associated pro-inflammatory signals, and viral or bacterial infections that compromise the blood-brain barrier.

It has been established that every neurological damage or disorder can lead to inflammation, which results in activation of resident microglia, accompanied by an increase in their number and change in phenotype. Acute neuronal damage resulting from stroke, hypoxia, and neurotrauma can compromise neuronal survival and indirectly trigger neuroinflammation. In these cases microglia are activated in response to the insult and adopt a phagocytic phenotype and release inflammatory mediators, such as cytokines and chemokines. This may be considered as a protective response to limit further injury and initiate repair processes.

Neuroinflammation Microglia

Microglia are located throughout the brain and spinal cord and may account for up to 15% of all cells in the brain. They are the first responders in active immune defense in the central nervous system. Their protective functions include scavenging plaques, damaged or superfluous neurons and synapses, and infectious agents to prevent potential fatal damage. Microglia play several crucial roles during brain development. They induce apoptosis of specific neuronal subpopulations and contribute to a numerical control of neuronal cells. They support synaptogenesis through the local synthesis of neurotrophic factors, and regulate synaptic transmission and remodeling. However, microglia may also play a detrimental role for neurons when they gain a chronic inflammatory function and promote neuropathologies.

Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis cause chronic neuroinflammation that persists long after an initial injury or insult and results in long-standing activation of microglia and sustained release of inflammatory mediators. These molecules increase oxidative stress and perpetuate the inflammatory cycle, activating additional microglia and promoting their proliferation. This results in further release of inflammatory factors. Hence, under chronic neuroinflammation, microglia activation has detrimental effects and forms the basis of microglial dysfunction hypothesis.

During Alzheimer’s disease progression microglia activation can either reduce the levels of Aβ peptides via phagocytosis, clearance, and degradation or release pro-inflammatory cytokines that can contribute to neuronal damage and loss. Generally, under physiological conditions, active microglia maintain homoeostasis and play a role in neuroprotection and repair by releasing growth factors, such as BDNF and TGF-b. However, under pathological conditions, such as infection, injury, and ischemia they are activated, proliferate, and assume a macrophage-like morphology.

Microglia Neuroinflammation style=

Activated microglia exert a variety of effects, which may be either neurotoxic or neuroprotective. For example, microglia activated by lipopolysaccharides, IFN-g or TNF-a, are known as the M1 or classically activated type and they play a vital role in the defense against pathogens and tumor cell by producing pro-inflammatory cytokines, such as IL-1β, TNF-α, and free radicals. However, the alternative M2 type of microglia have an anti-inflammatory phenotype, which promote tissue remodeling and repair and angiogenesis via the release of anti-inflammatory cytokines such as IL-4, and IL-10 and diminished levels of pro-inflammatory cytokines. In murine models of Alzheimer’s disease an increase in both M1 and M2 microglia have been reported compared to their age-matched controls and with the progression of disease microglia are shown to switch from M2 to M1 type. NALP3 inflammasome, a mediator of IL-1β production, plays an important role in driving the innate immune response towards Aβ peptides and blocking NALP3 activity can induce microglial phagocytosis and a shift towards the M2 phenotype.

An early expression of pro-inflammatory cytokines in Alzheimer’s disease brain by non-neuronal cells, including endothelial cells, can also play a role in the development of disease because microvessels in diseased brain can release high amounts of pro-inflammatory cytokine compared to their age-matched controls. In addition, sustained inflammation from the periphery may also contribute to uptake of pro-inflammatory cytokines in the brain, mediated by RAGE and compromised blood-brain barrier.

A better understanding on microglial physiology and the recognition that resident microglia in the brain can initiate pro-inflammatory immune responses, and the increasing evidence supporting the role of inflammatory cytokines and other mediators of inflammation could lead to newer therapeutic approaches for treatment of stroke and debilitating neurodegenerative diseases

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