title: Interleukin-1 as a phenotypic immunomodulator in keratinizing squamous metaplasia of the ocular surface in Sjögren's syndrome.
abstract: Chronic inflammation of the ocular surface in Sjögren's syndrome (SS) is associated with a vision-threatening, phenotypic change of the ocular surface, which converts from a nonkeratinized, stratified squamous epithelium to a nonsecretory, keratinized epithelium. This pathological process is known as squamous metaplasia. Based on a significant correlation between ocular surface interleukin (IL)-1beta expression and squamous metaplasia in patients with SS, we investigated the role of IL-1 in the pathogenesis of squamous metaplasia in an animal model that mimics the clinical characteristics of SS. Using autoimmune-regulator (aire)-deficient mice, we assessed lacrimal gland and ocular surface immunopathology by quantifying the infiltration of major histocompatibility complex class II(+) (I-A(d+)) dendritic cells and CD4(+) T cells. We examined squamous metaplasia using a biomarker of keratinization, small proline-rich protein 1B. We used lissamine green staining as a readout for ocular surface epitheliopathy and Alcian blue/periodic acid-Schiff histochemical analysis to characterize goblet cell muco-glycoconjugates. Within 8 weeks, the eyes of aire-deficient mice were pathologically keratinized with significant epithelial damage and altered mucin glycosylation. Although knockdown of IL-1 receptor 1 did not attenuate lymphocytic infiltration of the lacrimal gland or eye, it significantly reduced ocular surface keratinization, epitheliopathy, and muco-glycoconjugate acidification. These data demonstrate a phenotypic modulation role for IL-1 in the pathogenesis of squamous metaplasia and suggest that IL-1 receptor 1-targeted therapies may be beneficial for treating ocular surface disease associated with SS.
authors.affiliation: University of California, San Francisco, Francis I. Proctor Foundation, San Francisco, CA 94143, USA.
authors.forename: Ying-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Karina
authors.initials: K
authors.lastname: Nikulina
authors.forename: Stanislav
authors.initials: S
authors.lastname: Lazarev
authors.forename: Ahmad F
authors.initials: AF
authors.lastname: Bahrami
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Noble
authors.forename: Marianne
authors.initials: M
authors.lastname: Gallup
authors.forename: Nancy A
authors.initials: NA
authors.lastname: McNamara
mesh_terms: D000818:Animals; D002452:Cell Count; D005123:Eye / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005128:Eye Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000276:immunology* / Q000378:metabolism; D008679:Metaplasia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D007375:Interleukin-1