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TSLP Protects Corneas From Pseudomonas aeruginosa Infection by Regulating Dendritic Cells and IL-23-IL-17 Pathway.
Invest Ophthalmol Vis Sci 2018; 59(10):4228-4237IO

Abstract

Purpose

We sought to determine the role of epithelium-produced thymic stromal lymphopoietin (TSLP) and its underlying mechanisms in corneal innate immune defense against Pseudomonas (P.) aeruginosa keratitis.

Methods

The expression of TSLP and TSLPR in cultured human corneal epithelial cells (HCECs) and mouse corneas was determined by PCR, Western, and/or ELISA. Cellular localization of TSLP receptor (TSLPR) was determined by whole mount confocal microscopy. TSLP-TSLPR signaling was downregulated by neutralizing antibodies and/or small interfering (si)RNA; their effects on the severity of P. aeruginosa-keratitis and cytokine expression were assessed using clinical scoring, bacterial counting, PMN infiltration, and real-time PCR. The role of dendritic cells (DCs) in corneal innate immunity was determined by local DC depletion using CD11c-DTR mice.

Results

P. aeruginosa-infection induced the expression of TSLP and TSLPR in both cultured primary HCECs and in C57BL/6 mouse corneas. While TSLP was mostly expressed by epithelial cells, CD11c-positive cells were positive for TSLPR. Targeting TSLP or TSLPR with neutralizing antibodies or TSLPR with siRNA resulted in more severe keratitis, attributable to an increase in bacterial burden and PMN infiltration. TSLPR neutralization significantly suppressed infection-induced TSLP and interleukin (IL)-17C expression and augmented the expression of IL-23 and IL-17A. Local depletion of DCs markedly increased the severity of keratitis and exhibited no effects on TSLP and IL-23 expression while suppressing IL-17A and C expression in P. aeruginosa-infected corneas.

Conclusions

The epithelium-expressed TSLP plays a protective role in P. aeruginosa keratitis through targeting of DCs and in an IL-23/IL-17 signaling pathway-related manner.

Authors+Show Affiliations

Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States. Eye and ENT Hospital of Fudan University, Xuhui District, Shanghai, China.Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States.Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States.Eye and ENT Hospital of Fudan University, Xuhui District, Shanghai, China.Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30128494

Citation

Cui, Xinhan, et al. "TSLP Protects Corneas From Pseudomonas Aeruginosa Infection By Regulating Dendritic Cells and IL-23-IL-17 Pathway." Investigative Ophthalmology & Visual Science, vol. 59, no. 10, 2018, pp. 4228-4237.
Cui X, Gao N, Me R, et al. TSLP Protects Corneas From Pseudomonas aeruginosa Infection by Regulating Dendritic Cells and IL-23-IL-17 Pathway. Invest Ophthalmol Vis Sci. 2018;59(10):4228-4237.
Cui, X., Gao, N., Me, R., Xu, J., & Yu, F. X. (2018). TSLP Protects Corneas From Pseudomonas aeruginosa Infection by Regulating Dendritic Cells and IL-23-IL-17 Pathway. Investigative Ophthalmology & Visual Science, 59(10), pp. 4228-4237. doi:10.1167/iovs.18-24672.
Cui X, et al. TSLP Protects Corneas From Pseudomonas Aeruginosa Infection By Regulating Dendritic Cells and IL-23-IL-17 Pathway. Invest Ophthalmol Vis Sci. 2018 08 1;59(10):4228-4237. PubMed PMID: 30128494.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TSLP Protects Corneas From Pseudomonas aeruginosa Infection by Regulating Dendritic Cells and IL-23-IL-17 Pathway. AU - Cui,Xinhan, AU - Gao,Nan, AU - Me,Rao, AU - Xu,Jianjiang, AU - Yu,Fu-Shin X, PY - 2018/8/22/entrez PY - 2018/8/22/pubmed PY - 2019/4/6/medline SP - 4228 EP - 4237 JF - Investigative ophthalmology & visual science JO - Invest. Ophthalmol. Vis. Sci. VL - 59 IS - 10 N2 - Purpose: We sought to determine the role of epithelium-produced thymic stromal lymphopoietin (TSLP) and its underlying mechanisms in corneal innate immune defense against Pseudomonas (P.) aeruginosa keratitis. Methods: The expression of TSLP and TSLPR in cultured human corneal epithelial cells (HCECs) and mouse corneas was determined by PCR, Western, and/or ELISA. Cellular localization of TSLP receptor (TSLPR) was determined by whole mount confocal microscopy. TSLP-TSLPR signaling was downregulated by neutralizing antibodies and/or small interfering (si)RNA; their effects on the severity of P. aeruginosa-keratitis and cytokine expression were assessed using clinical scoring, bacterial counting, PMN infiltration, and real-time PCR. The role of dendritic cells (DCs) in corneal innate immunity was determined by local DC depletion using CD11c-DTR mice. Results: P. aeruginosa-infection induced the expression of TSLP and TSLPR in both cultured primary HCECs and in C57BL/6 mouse corneas. While TSLP was mostly expressed by epithelial cells, CD11c-positive cells were positive for TSLPR. Targeting TSLP or TSLPR with neutralizing antibodies or TSLPR with siRNA resulted in more severe keratitis, attributable to an increase in bacterial burden and PMN infiltration. TSLPR neutralization significantly suppressed infection-induced TSLP and interleukin (IL)-17C expression and augmented the expression of IL-23 and IL-17A. Local depletion of DCs markedly increased the severity of keratitis and exhibited no effects on TSLP and IL-23 expression while suppressing IL-17A and C expression in P. aeruginosa-infected corneas. Conclusions: The epithelium-expressed TSLP plays a protective role in P. aeruginosa keratitis through targeting of DCs and in an IL-23/IL-17 signaling pathway-related manner. SN - 1552-5783 UR - https://www.unboundmedicine.com/medline/citation/30128494/TSLP_Protects_Corneas_From_Pseudomonas_aeruginosa_Infection_by_Regulating_Dendritic_Cells_and_IL_23_IL_17_Pathway_ L2 - http://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.18-24672 DB - PRIME DP - Unbound Medicine ER -