title: Ocular inflammation induces trigeminal pain, peripheral and central neuroinflammatory mechanisms.
abstract: Ocular surface diseases are among the most frequent ocular pathologies, with prevalence ranging from 20% of the general population. In addition, ocular pain following corneal injury is frequently observed in clinic. The aim of the study was to characterize the peripheral and central neuroinflammatory process in the trigeminal pathways in response to cornea alteration induced by chronic topical instillations of 0.2% benzalkonium chloride (BAC) in male C57BL/6J mice. In vitro BAC induced neurotoxicity and increases neuronal (FOS, ATF3) and pro-inflammatory (IL-6) markers in primary mouse trigeminal ganglion culture. BAC-treated mice exhibited 7days after the treatment reduced aqueous tear production and increased inflammatory cell infiltration in the cornea. Hypertonic saline-evoked eye wipe behavior was enhanced in BAC-treated animals that exhibited increased FOS, ATF3 and Iba1 immunoreactivity in the trigeminal ganglion. Ocular inflammation is associated with a significant increase in IL-6 and TNF-α mRNA expression in the trigeminal ganglion. We reported a strong increase in FOS and Iba1 positive cells in particular in the sensory trigeminal complex at the ipsilateral interpolaris/caudalis (Vi/Vc) transition and Vc/upper cervical cord (Vc/C1) regions. In addition, activated microglial cells were tightly wrapped around activated FOS neurons in both regions and phosphorylated p38 mitogen-activated protein kinase was markedly enhanced specifically in microglial cells during ocular inflammation. Similar data were obtained in the facial motor nucleus. These neuroanatomical data correlated with the increase in mRNA expression of pro-inflammatory (TNF-α, IL-6, CCL2) and neuronal (FOS and ATF3) markers. Interestingly, the suppression of corneal inflammation 10days following the end of BAC treatment resulted in a marked attenuation of peripheral and central changes observed in pathological conditions. This study provides the first demonstration that corneal inflammation induces activation of neurons and microglial p38 MAPK pathway within sensory trigeminal complex. These results suggest that this altered activity in intracellular signaling caused by ocular inflammation might play a priming role in the central sensitization of ocular related brainstem circuits, which represents a significant factor in ocular pain development.
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France.
authors.forename: Pierre-Serge
authors.initials: PS
authors.lastname: Launay
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Reboussin
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris F-75012, France.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Kessal
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France.
authors.forename: David
authors.initials: D
authors.lastname: Godefroy
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France.
authors.forename: William
authors.initials: W
authors.lastname: Rostene
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris F-75012, France.
authors.forename: Jose-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris F-75012, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Baudouin
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Melik Parsadaniantz
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, Université UPMC, Paris 06, UM 80, Institut de la Vision, 75012 Paris, France; CNRS, UMR 7210, Paris F-75012, France. Electronic address: annabelle.reaux@inserm.fr.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Reaux Le Goazigo
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000633:toxicity; D001548:Benzalkonium Compounds / Q000633:toxicity; D003315:Cornea / Q000473:pathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology*; D005131:Eye Injuries / Q000139:chemically induced / Q000150:complications*; D005133:Eye Movements / Q000187:drug effects / Q000502:physiology; D007839:Functional Laterality / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009443:Neuritis / Q000209:etiology*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000187:drug effects; D014277:Trigeminal Neuralgia / Q000209:etiology*
chemical_list: D000891:Anti-Infective Agents, Local; D001548:Benzalkonium Compounds; D005904:Glial Fibrillary Acidic Protein; D016761:Oncogene Proteins v-fos
keywords: Benzalkonium chloride; Corneal neurons; Facial motor nucleus; Neuroinflammation; Ocular pain; Trigeminal complex