title: Suppression of Toll-like receptor-mediated innate immune responses at the ocular surface by the membrane-associated mucins MUC1 and MUC16.
abstract: Membrane-associated mucins (MAMs) expressed on the ocular surface epithelium form a dense glycocalyx that is hypothesized to protect the cornea and conjunctiva from external insult. In this study, the hypothesis that the MAMs MUC1 and MUC16, expressed on the apical surface of the corneal epithelium, suppress Toll-like receptor (TLR)-mediated innate immune responses was tested. Using an in vitro model of corneal epithelial cells that are cultured to express MAMs, we show that reduced expression of either MUC1 or MUC16 correlates with increased message and secreted protein levels of the proinflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) following exposure of cells to the TLR2 and TLR5 agonists, heat-killed Listeria monocytogenes and flagellin, respectively. As mice express Muc1 (but not Muc16) in the corneal epithelium, a Muc1(-/-) mouse model was used to extend in vitro findings. Indeed, IL-6 and TNF-α message levels were increased in the corneal epithelium of Muc1(-/-) mice, in comparison with wild-type mice, following exposure of enucleated eyes to the TLR2 and TLR5 agonists. Our results suggest that the MAMs MUC1 and MUC16 contribute to the maintenance of immune homeostasis at the ocular surface by limiting TLR-mediated innate immune responses.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: B B
authors.initials: BB
authors.lastname: Menon
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kaiser-Marko
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: S
authors.initials: S
authors.lastname: Spurr-Michaud
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Tisdale
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: I K
authors.initials: IK
authors.lastname: Gipson
mesh_terms: D000818:Animals; D018394:CA-125 Antigen / Q000235:genetics / Q000276:immunology*; D002461:Cell Line, Transformed; D003228:Conjunctiva / Q000276:immunology* / Q000382:microbiology; D003315:Cornea / Q000276:immunology* / Q000382:microbiology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology*
chemical_list: D018394:CA-125 Antigen; D016207:Cytokines; C060192:MUC1 protein, human; C451759:MUC16 protein, human; C534798:MUC16 protein, mouse; D008565:Membrane Proteins; D018396:Mucin-1; C495342:TLR2 protein, human; C495346:TLR5 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; C577056:muc1 protein, mouse