Microglial migration and interactions with dendrimer nanoparticles are altered in the presence of neuroinflammation
Fan Zhang1,2, Elizabeth Nance1,3,4, Yossef Alnasser3
1Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
Background:
Microglial 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.
Methods:
To 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.
Results:
Microglial 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.
Conclusions:
This 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.
Insights
Maternal inflammation impairs newborn brain microglial function and movement, potentially contributing to cerebral palsy (CP). However, these "impaired" microglia show increased dendrimer uptake, offering a target for therapeutic delivery.
Area of Science:
- Neuroscience
- Immunology
- Nanotechnology
Background:
- Microglial cells are key in neuroinflammation, impacting disorders like cerebral palsy (CP) and autism.
- Pro-inflammatory activation impairs microglial neuroprotective functions, causing persistent immune dysregulation.
- Dendrimer delivery of anti-inflammatory agents can reduce inflammation and improve motor function in CP models by targeting activated microglia.
Purpose of the Study:
- To investigate microglial-dendrimer interactions in a model of maternal inflammation-induced CP.
- To analyze microglial migration dynamics and dendrimer uptake in the presence of neuroinflammation using an ex vivo brain slice model.
Main Methods:
- Created organotypic whole-hemisphere brain slice cultures from newborn rabbits exposed to in utero inflammation.
- Analyzed microglial morphology, migration (distance and velocity), and dendrimer uptake in inflamed versus healthy control brain slices.
Main Results:
- Microglia in CP model exhibited amoeboid morphology and impaired migration (decreased distance and velocity).
- Despite impaired migration, these microglia demonstrated significantly greater and faster dendrimer uptake compared to controls.
- This suggests a potential for targeted drug delivery to dysregulated microglia.
Conclusions:
- Maternal intrauterine inflammation impairs neonatal microglial function and motility, contributing to brain injury and CP.
- Enhanced dendrimer uptake by impaired microglia presents a therapeutic strategy for targeted drug delivery.
- Dendrimer-based nanotherapeutics require consideration of host tissue and target cell properties for efficacy.
- The ex vivo model serves as a rapid screening tool for evaluating therapies targeting microglial function.
