Targeting chronic and evolving neuroinflammation following traumatic brain injury to improve long-term outcomes: insights from microglial-depletion models.

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Authors: Rebecca Henry and David Loane
Date: May 2021
From: Neural Regeneration Research(Vol. 16, Issue 5)
Publisher: Medknow Publications and Media Pvt. Ltd.
Document Type: Article
Length: 2,011 words
Lexile Measure: 1700L

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Byline: Rebecca. Henry, David. Loane

Microglia, the resident innate immune cells of the central nervous system (CNS), play important roles in brain development, maintenance, and disease. As brain sentinels, microglia adopt a surveillant state in healthy tissue characterized by a ramified scanning morphology that maintains CNS homeostasis and contributes to learning-associated synaptic plasticity. Following acute CNS injury or during chronic disease, microglia undergo dramatic morphological transformations and a phenotypic switch to an activated state that initially plays an important protective role against pathological insult (e.g., clearance of cellular debris by phagocytosis to facilitate effective wound healing responses). However, when microglial activation becomes chronic and dysregulated it can have detrimental effects and lead to neurodegenerative processes. Chronic microglial activation has been reported in patients who suffer moderate-to-severe traumatic brain injury (TBI) and is evident in white matter and distant sites from the primary lesion for many years after the initial brain trauma (Johnson et al., 2013). Microglia are also chronically activated up to 1 year following experimental TBI in rodents, and contribute to chronic neurodegeneration and cognitive impairments (Loane et al., 2014). Thus, chronic non-resolving inflammation with widespread microglial activation is a defining feature of moderate-to-severe TBI, and an important secondary injury mechanism that may be treatable (Simon et al., 2017).

Microglial development and long-term survival is dependent on colony stimulating factor 1 receptor (CSF1R), whereby CSF1R knockout mice are devoid of microglia and die before adulthood. The recent development of CNS-penetrant drugs that inhibit CSF1R to eliminate microglia has enabled the direct investigation of microglial function in the healthy and diseased CNS. When first generation CSF1R inhibitors, PLX3397, were administered to mice for a period of 21 days it led to robust brainwide elimination of microglia (> 95%) (Elmore et al., 2014). Moreover, upon removal of PLX3397 there was a rapid self-renewal and repopulation of microglia in brain, and repopulated cells were capable of mounting an inflammatory response similar to that of non-depleted microglia. A second generation and more selective CSF1R inhibitor, PLX5622, has been developed and has excellent pharmacokinetic properties, including oral bioavailability with a > 20% brain penetrance across multiple species (Spangenberg et al., 2019). PLX5622 rapidly eliminates microglia in brain within 7 days of treatment and can sustain depletion for many months. These new pharmacological tools have propelled much recent preclinical research into microglia depletion strategies as translational therapies for neurological diseases. Accordingly, there is now accumulating evidence that microglial depletion has a broad range of neuroprotective effects by reducing damaging microglial-mediated neuroinflammation (Han et al., 2019). For example, selective removal of microglia in Alzheimer's disease mouse models improves cognitive function, reduces neuronal loss, and partially prevents the progression of Alzheimer's disease pathology, but has no effects on amyloid levels and plaque loads. Furthermore, in autoimmune disorders such as Multiple Sclerosis microglial depletion reduces disease progression in experimental autoimmune encephalomyelitis models, and enhances remyelination and recovery in a cuprizone demyelination mouse model.

In experimental brain injury models, differential effects of microglia depletion have been reported under varying...

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Gale Document Number: GALE|A642710641