Abstract
BackgroundMicroglial cells have been implicated in neuroinflammation-mediated injury in the brain, including neurodevelopmental disorders such as cerebral palsy (CP) and autism. Pro-inflammatory activation of microglial cells results in the impairment of their neuroprotective functions, leading to an exaggerated, ongoing immune dysregulation that can persist long after the initial insult. We have previously shown that dendrimer-mediated delivery of an anti-inflammatory agent can attenuate inflammation in a rabbit model of maternal inflammation-induced CP and significantly improve the motor phenotype, due to the ability of the dendrimer to selectively localize in activated microglia.MethodsTo elucidate the interactions between dendrimers and microglia, we created an organotypic whole-hemisphere brain slice culture model from newborn rabbits with and without exposure to inflammation in utero. We then used this model to analyze the dynamics of microglial migration and their interactions with dendrimers in the presence of neuroinflammation.ResultsMicroglial cells in animals with CP had an amoeboid morphology and impaired cell migration, demonstrated by decreased migration distance and velocity when compared to cells in healthy, age-matched controls. However, this decreased migration was associated with a greater, more rapid dendrimer uptake compared to microglial cells from healthy controls.ConclusionsThis study demonstrates that maternal intrauterine inflammation is associated with impaired microglial function and movement in the newborn brain. This microglial impairment may play a role in the development of ongoing brain injury and CP in the offspring. Increased uptake of dendrimers by the “impaired” microglia can be exploited to deliver drugs specifically to these cells and modulate their functions. Host tissue and target cell characteristics are important aspects to be considered in the design and evaluation of targeted dendrimer-based nanotherapeutics for improved and sustained efficacy. This ex vivo model also provides a rapid screening tool for evaluation of the effects of various therapies on microglial function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0529-3) contains supplementary material, which is available to authorized users.
Highlights
Microglial cells have been implicated in neuroinflammation-mediated injury in the brain, including neurodevelopmental disorders such as cerebral palsy (CP) and autism
We found that inflammation led to impairment in the surveillance function of microglial cells, as demonstrated by hindered migration of microglial cells in the brain of newborn kits with CP compared to healthy control kits
To validate whether the acute study allowed the preservation of in vivo pathology of microglial cells, we evaluated the differences in microglial morphology between CP and healthy control kits over time in brain slices by quantifying microglial surface area to volume (S/V) ratio (Fig. 2)
Summary
Microglial cells have been implicated in neuroinflammation-mediated injury in the brain, including neurodevelopmental disorders such as cerebral palsy (CP) and autism. Microglial cells are the primary resident immune cells in the central nervous system (CNS). Their migration dynamics are associated with their functions in the CNS [1,2,3]. In response to any acute brain injury or damage, these surveying microglial cells can rapidly transform into an activated state and migrate to the injury site [5,6,7,8]. In neurodevelopmental disorders such as cerebral palsy (CP), where activated microglial cells have been implicated, the migration dynamics of microglial cells are not well-understood [9]. Microglial migration dynamics in a more representative biological environment, such as the brain parenchyma, especially in the presence of pathology, have not been adequately explored
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