title: Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.
abstract: BACKGROUND
  TGF-β is a pleiotropic cytokine that can have pro- or anti-inflammatory effects depending on the context. Elevated levels of bioactive TGF-β1 in tears and elevated TGF-β1mRNA transcripts in conjunctiva and minor salivary glands of human Sjögren's Syndrome patients has also been reported. The purpose of this study was to evaluate the response to desiccating stress (DS), an experimental model of dry eye, in dominant-negative TGF-β type II receptor (CD4-DNTGFβRII) mice. These mice have a truncated TGF-β receptor in CD4(+) T cells, rendering them unresponsive to TGF-β.
  
  
  RESULTS
  DS was induced by subcutaneous injection of scopolamine and exposure to a drafty low humidity environment in CD4-DNTGFβRII and wild-type (WT) mice, aged 14 weeks, for 5 days. Nonstressed (NS) mice served as controls. Parameters of ocular surface disease included corneal smoothness, corneal barrier function and conjunctival goblet cell density. NS CD4-DNTGFβRII at 14 weeks of age mice exhibited a spontaneous dry eye phenotype; however, DS improved their corneal barrier function and corneal surface irregularity, increased their number of PAS+ GC, and lowered CD4(+) T cell infiltration in conjunctiva. In contrast to WT, CD4-DNTGFβRII mice did not generate a Th-17 and Th-1 response, and they failed to upregulate MMP-9, IL-23, IL-17A, RORγT, IFN-γ and T-bet mRNA transcripts in conjunctiva. RAG1KO recipients of adoptively transferred CD4+T cells isolated from DS5 CD4-DNTGFβRII showed milder dry eye phenotype and less conjunctival inflammation than recipients of WT control.
  
  
  CONCLUSIONS
  Our results showed that disruption of TGF-β signaling in CD4(+) T cells causes paradoxical improvement of dry eye disease in mice subjected to desiccating stress.
authors.affiliation: Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, United States of America. cintiadp@bcm.tmc.edu
authors.forename: Cintia S
authors.initials: CS
authors.lastname: De Paiva
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Volpe
authors.forename: Niral B
authors.initials: NB
authors.lastname: Gandhi
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Zheng
authors.forename: John D
authors.initials: JD
authors.lastname: Pitcher
authors.forename: William J
authors.initials: WJ
authors.lastname: Farley
authors.forename: Michael E
authors.initials: ME
authors.lastname: Stern
authors.forename: Jerry Y
authors.initials: JY
authors.lastname: Niederkorn
authors.forename: De-Quan
authors.initials: DQ
authors.lastname: Li
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pflugfelder
mesh_terms: D019264:Adoptive Transfer; D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003228:Conjunctiva / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015352:Dry Eye Syndromes / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005123:Eye / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005799:Genes, Dominant / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007638:Keratoconjunctivitis Sicca / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D019707:Receptors, Chemokine / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018398:Homeodomain Proteins; D019707:Receptors, Chemokine; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C064658:RAG-1 protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II