title: EMMPRIN modulates epithelial barrier function through a MMP-mediated occludin cleavage: implications in dry eye disease.
abstract: Dry eye is a common disease that develops as a result of alteration of tear fluid, leading to osmotic stress and a perturbed epithelial barrier. Matrix metalloproteinase-9 (MMP-9) may be important in dry eye disease, as its genetic knockout conferred resistance to the epithelial disruption. We show that extracellular matrix metalloproteinase inducer (EMMPRIN; also termed CD147), an inducer of MMP expression, participates in the pathogenesis of dry eye through MMP-mediated cleavage of occludin, an important component of tight junctions. EMMPRIN expression was increased on the ocular surface of dry eye patients and correlated with those of MMP-9. High osmolarity in cell culture, mimicking dry eye conditions, increased both EMMPRIN and MMP-9 and resulted in the disruption of epithelial junctions through the cleavage of occludin. Exogenously added recombinant EMMPRIN had similar effects that were abrogated in the presence of the MMP inhibitor marimastat. Membrane occludin immunostaining was markedly increased in the apical corneal epithelium of both EMMPRIN and MMP-9 knock-out mice. Furthermore, an inverse correlation between EMMPRIN and occludin membrane staining was consistently observed both in vitro and in vivo as a function of corneal epithelial cells differentiation. These data suggest a possible role of EMMPRIN in regulating the amount of occludin at the cell surface in homeostasis beyond pathological situations such as dry eye disease, and EMMPRIN may be essential for the formation and maintenance of organized epithelial structure.
authors.affiliation: CRRET Laboratory, Université Paris-Est, CNRS, Créteil, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Huet
authors.forename: Benoit
authors.initials: B
authors.lastname: Vallée
authors.forename: Jean
authors.initials: J
authors.lastname: Delbé
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
authors.forename: Virginie
authors.initials: V
authors.lastname: Prulière-Escabasse
authors.forename: Magali
authors.initials: M
authors.lastname: Tremouilleres
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.forename: Serge
authors.initials: S
authors.lastname: Doan
authors.forename: Christophe
authors.initials: C
authors.lastname: Baudouin
authors.forename: Suzanne
authors.initials: S
authors.lastname: Menashi
authors.forename: Eric E
authors.initials: EE
authors.lastname: Gabison
mesh_terms: D000818:Animals; D051926:Basigin / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation; D015352:Dry Eye Syndromes / Q000209:etiology* / Q000378:metabolism; D019573:Epithelium, Corneal / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D062793:Occludin; D009994:Osmolar Concentration; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D011994:Recombinant Proteins; D051926:Basigin