title: Microglial migration and interactions with dendrimer nanoparticles are altered in the presence of neuroinflammation.
abstract: 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.
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.|Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.|Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.|Present address: Department of Chemical Engineering, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nance
authors.affiliation: Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
authors.forename: Yossef
authors.initials: Y
authors.lastname: Alnasser
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.|Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.|Hugo Moser Research Center, Kennedy Krieger Institute, Baltimore, MD, 21205, USA.
authors.forename: Rangaramanujam
authors.initials: R
authors.lastname: Kannan
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA. skannan3@jhmi.edu.|Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. skannan3@jhmi.edu.|Hugo Moser Research Center, Kennedy Krieger Institute, Baltimore, MD, 21205, USA. skannan3@jhmi.edu.|Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. skannan3@jhmi.edu.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Kannan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D050091:Dendrimers / Q000633:toxicity*; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D017628:Microglia / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D053758:Nanoparticles / Q000633:toxicity*; D009924:Organ Culture Techniques; D011247:Pregnancy; D011817:Rabbits
chemical_list: D050091:Dendrimers
keywords: Cell migration; Dendrimer; Inflammation; Microglia; Morphology