Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.

<h4>Background</h4>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...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Cintia S De Paiva, Eugene A Volpe, Niral B Gandhi, Xiaobo Zhang, Xiaofen Zheng, John D Pitcher, William J Farley, Michael E Stern, Jerry Y Niederkorn, De-Quan Li, Richard A Flavell, Stephen C Pflugfelder
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2011
Materias:
R
Q
Acceso en línea:https://doaj.org/article/60dc5f26b15249c1a0229a4f9063c6a7
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:60dc5f26b15249c1a0229a4f9063c6a7
record_format dspace
spelling oai:doaj.org-article:60dc5f26b15249c1a0229a4f9063c6a72021-11-18T07:32:07ZDisruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.1932-620310.1371/journal.pone.0029017https://doaj.org/article/60dc5f26b15249c1a0229a4f9063c6a72011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22194977/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Cintia S De PaivaEugene A VolpeNiral B GandhiXiaobo ZhangXiaofen ZhengJohn D PitcherWilliam J FarleyMichael E SternJerry Y NiederkornDe-Quan LiRichard A FlavellStephen C PflugfelderPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 12, p e29017 (2011)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Cintia S De Paiva
Eugene A Volpe
Niral B Gandhi
Xiaobo Zhang
Xiaofen Zheng
John D Pitcher
William J Farley
Michael E Stern
Jerry Y Niederkorn
De-Quan Li
Richard A Flavell
Stephen C Pflugfelder
Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.
description <h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format article
author Cintia S De Paiva
Eugene A Volpe
Niral B Gandhi
Xiaobo Zhang
Xiaofen Zheng
John D Pitcher
William J Farley
Michael E Stern
Jerry Y Niederkorn
De-Quan Li
Richard A Flavell
Stephen C Pflugfelder
author_facet Cintia S De Paiva
Eugene A Volpe
Niral B Gandhi
Xiaobo Zhang
Xiaofen Zheng
John D Pitcher
William J Farley
Michael E Stern
Jerry Y Niederkorn
De-Quan Li
Richard A Flavell
Stephen C Pflugfelder
author_sort Cintia S De Paiva
title Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.
title_short Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.
title_full Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.
title_fullStr Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.
title_full_unstemmed Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.
title_sort disruption of tgf-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca.
publisher Public Library of Science (PLoS)
publishDate 2011
url https://doaj.org/article/60dc5f26b15249c1a0229a4f9063c6a7
work_keys_str_mv AT cintiasdepaiva disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT eugeneavolpe disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT niralbgandhi disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT xiaobozhang disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT xiaofenzheng disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT johndpitcher disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT williamjfarley disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT michaelestern disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT jerryyniederkorn disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT dequanli disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT richardaflavell disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
AT stephencpflugfelder disruptionoftgfbsignalingimprovesocularsurfaceepithelialdiseaseinexperimentalautoimmunekeratoconjunctivitissicca
_version_ 1718423287538647040