title: Ocular surface injury induces inflammation in the brain: in vivo and ex vivo evidence of a corneal-trigeminal axis.
abstract: OBJECTIVE
  To test whether a corneal injury can stimulate inflammation in the trigeminal ganglion (TG), a structure located in the brain.
  
  
  METHODS
  At 4 and 8 days after alkali burn induced in the right eyes of mice, in vivo magnetic resonance imaging (MRI) of the brain was done before and after ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) contrast to track macrophages. Trigeminal ganglia were stained for Prussian Blue and inflammatory cell markers. Interleukin-1β, TNF-α, and VEGF-A transcripts were quantified on days 1, 4, and 8, and 4 days after corneal topical anti-inflammatory treatment with 0.2% dexamethasone. The expression of Substance P and its receptor NK-1R was also measured in the TG on day 4.
  
  
  RESULTS
  Corneal alkali burn induced leukocyte infiltration, including T cells, in the right TG at 4 and 8 days. In vivo MRI showed an increased contrast uptake in the right TG, which peaked at day 8. Prussian Blue(+) USPIO(+) macrophages were observed in the right TG and exhibited an M2 phenotype. The M2-macrophage infiltration was preponderant in the TG after damage. The proinflammatory cytokines Substance P and NK-1R were significantly increased in both the TGs. The expression of IL-1β and VEGF-A was significantly reduced in the right TG with dexamethasone treatment.
  
  
  CONCLUSIONS
  We suggest, for the first time, inflammatory involvement of brain structures following ocular surface damage. Our findings support the hypothesis that the neuropeptide Substance P may be involved in the propagation of inflammation from the cornea to the TG through corneal nerves.
authors.affiliation: Eye Repair Lab, Division of Neuroscience, Cornea and Ocular Surface Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Eye Repair Lab, Division of Neuroscience, Cornea and Ocular Surface Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Bignami
authors.affiliation: Eye Repair Lab, Division of Neuroscience, Cornea and Ocular Surface Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giacomini
authors.affiliation: Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Capitolo
authors.affiliation: Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Chaabane
authors.affiliation: Eye Repair Lab, Division of Neuroscience, Cornea and Ocular Surface Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rama
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003315:Cornea / Q000378:metabolism / Q000473:pathology*; D065306:Corneal Injuries / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005126:Eye Burns / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012668:Trigeminal Ganglion / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D012313:RNA
keywords: cornea; in vivo MRI; inflammation; macrophages; trigeminal ganglion