Microglial Activation in Traumatic Brain Injury

Abstract

Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.

TLR4-pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury

“…Our data give evidence that the CHI model of TBI employed in this study induces a subtype of reactive microglia and astrocytes with "harmful" effects that might well correspond to the M1 and A1 reactive cells. The control of microglial inflammation exerts neuroprotective effects and has been extensively studied using several models in the last years (10,46,47). But our data support that both microglia and astrocytes are important in the pathophysiology of brain injuries since pharmacological TLR4 blockade and genetically nonactive astrocytes from IP 3 R2 -/have the opposite response.…”

“…Under pathological conditions or after an injury, microglia is rapidly activated and initiates an inflammatory response to restore tissue homeostasis. In addition, microglia activation determines the fate of astrocytes by releasing a plethora of signaling factors that induce reactive astrogliosis and regulate astrocytic immune reactions (10,11). On the other hand, activated astrocytes-derived factors also trigger microglial activation and control their cellular functions (12).…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Apart from beneficial roles in the development of CNS, microglia can be widely involved in various types of neurological disorders, including stroke (Guruswamy & ElAli, ; Kronenberg et al, ), multiple sclerosis (MS) (Bogie, Stinissen, & Hendriks, ; Luo et al, ), AD (Hansen, Hanson, & Sheng, ; Sarlus & Heneka, ), PD (Subramaniam & Federoff, ), sleep disorders (Nadjar, Wigren, & Tremblay, ), amyotrophic lateral sclerosis (ALS) (Geloso et al, ; Liu & Wang, ), Huntington's disease (H. M. Yang, Yang, Huang, Tang, & Guo, ), epilepsy (Eyo, Murugan, & Wu, ; Zhao, Liao, et al, ), gliomas (Hambardzumyan, Gutmann, & Kettenmann, ; Schiffer, Mellai, Bovio, & Annovazzi, ), Prion diseases (Aguzzi & Zhu, ; Obst, Simon, Mancuso, & Gomez‐Nicola, ), psychiatric disorders (Mondelli, Vernon, Turkheimer, Dazzan, & Pariante, ; Prinz & Priller, ; Setiawan et al, ; Singhal & Baune, ), neuropathic pain (Inoue & Tsuda, ; Peng et al, ), adrenomyeloneuropathy (Gong et al, ), and traumatic brain injury (Donat, Scott, Gentleman, & Sastre, ). In general, microglia can be rapidly activated depending upon different stimulatory contexts and environmental changes through diverse molecular and cellular programs, subsequently transforming into the activated state and enhancing the expression of the Toll‐like receptors which sensitively bind microbial structures (Arcuri et al, ).…”

“…In this way microglial cells may prevent a return to normal homeostatic function. Conversely, if chronic inflammation mediated by persistent dysfunction of microglia remains after injury, this could lead to further extensive tissue damage, neuronal loss and cognitive deficits (Donat et al, ). In summary, although microglia are essential for the development and normal function of the CNS, dysregulated microglia contribute to disease severity in various neurological pathologies.…”

Developmental roles of microglia: A window into mechanisms of disease

“…). As CNS remodelers, microglia are also essential players in injury such as stroke (Benakis et al, ; Guruswamy and ElAli, ) and traumatic brain injury (Donat et al, ), as well as regeneration (Carpentier and Palmer, ; Martino et al, ; Kokaia et al, ). Following injury, microglia can also be both helpful and harmful, in part dependent on their phenotype (Xu et al, ).…”