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Interferon regulatory factor-1 in flagellin-induced reprogramming: potential protective role of CXCL10 in cornea innate defense against Pseudomonas aeruginosa infection.
Invest Ophthalmol Vis Sci 2013; 54(12):7510-21IO

Abstract

PURPOSE

We previously showed that pre-exposure of the cornea to Toll-like receptor (TLR)5 ligand flagellin induces strong protective innate defense against microbial pathogens and hypothesized that flagellin modulates gene expression at the transcriptional levels. Thus, we sought to determine the role of one transcription factor, interferon regulatory factor (IRF1), and its target gene CXCL10 therein.

METHODS

Superarray was used to identify transcription factors differentially expressed in Pseudomonas aeruginosa-challenged human corneal epithelial cells (CECs) with or without flagellin pretreatment. The expression of CXCL10, IRF1, LI-8(CXCL2), and IFNγ was determined by PCR, immunohistochemistry, Western/dot blotting, and/or ELISA. IRF1 knockout mice, CXCL10 and IFNγ neutralization, and NK cell depletion were used to define in vivo regulation and function of CXCL10. The severity of P. aeruginosa was assessed using clinical scoring, slit-lamp microscopy, bacterial counting, polymorphonuclear leukocytes (PMN) infiltration, and macrophage inflammatory protein 2/Chemokine (C-X-C motif) ligand 2 (MIP-2/CXCL2) expression.

RESULTS

Flagellin pretreatment drastically affected P. aeruginosa-induced IRF1 expression in human CECs. However, flagellin pretreatment augmented the P. aeruginosa-induced expression of Irf1 and its target gene Cxcl10 in B6 mouse corneas. Irf1 deficiency reduced infection-triggered CXCL10 expression, increased keratitis severity, and attenuated flagellin-elicited protection compared to values in wild-type (WT) controls. CXCL10 neutralization in the cornea of WT mice displayed pathogenesis similar to that of IRF1⁻/⁻ mice. IFNγ receptor neutralization and NK cell depletion prevented flagellin-augmented IRF1 and CXCL10 expression and increased the susceptibility to P. aeruginosa infection in mouse corneas.

CONCLUSIONS

IRF1 plays a role in the corneal innate immune response by regulating CXCL10 expression. IFNγ-producing NK cells augment the epithelial expression of IRF1 and CXCL10 and thus contribute to the innate defense of the cornea against P. aeruginosa infection.

Authors+Show Affiliations

Department of Anatomy and Cell Biology, Kresge Eye Institute, Wayne State University, Detroit, Michigan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

24130180

Citation

Yoon, Gi Sang, et al. "Interferon Regulatory Factor-1 in Flagellin-induced Reprogramming: Potential Protective Role of CXCL10 in Cornea Innate Defense Against Pseudomonas Aeruginosa Infection." Investigative Ophthalmology & Visual Science, vol. 54, no. 12, 2013, pp. 7510-21.
Yoon GS, Dong C, Gao N, et al. Interferon regulatory factor-1 in flagellin-induced reprogramming: potential protective role of CXCL10 in cornea innate defense against Pseudomonas aeruginosa infection. Invest Ophthalmol Vis Sci. 2013;54(12):7510-21.
Yoon, G. S., Dong, C., Gao, N., Kumar, A., Standiford, T. J., & Yu, F. S. (2013). Interferon regulatory factor-1 in flagellin-induced reprogramming: potential protective role of CXCL10 in cornea innate defense against Pseudomonas aeruginosa infection. Investigative Ophthalmology & Visual Science, 54(12), pp. 7510-21. doi:10.1167/iovs.13-12453.
Yoon GS, et al. Interferon Regulatory Factor-1 in Flagellin-induced Reprogramming: Potential Protective Role of CXCL10 in Cornea Innate Defense Against Pseudomonas Aeruginosa Infection. Invest Ophthalmol Vis Sci. 2013 Nov 15;54(12):7510-21. PubMed PMID: 24130180.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interferon regulatory factor-1 in flagellin-induced reprogramming: potential protective role of CXCL10 in cornea innate defense against Pseudomonas aeruginosa infection. AU - Yoon,Gi Sang, AU - Dong,Chen, AU - Gao,Nan, AU - Kumar,Ashok, AU - Standiford,Theodore J, AU - Yu,Fu-Shin X, Y1 - 2013/11/15/ PY - 2013/10/17/entrez PY - 2013/10/17/pubmed PY - 2014/1/25/medline KW - CXCL10 KW - IRF1 KW - cell reprogramming KW - inflammation KW - toll-like receptors SP - 7510 EP - 21 JF - Investigative ophthalmology & visual science JO - Invest. Ophthalmol. Vis. Sci. VL - 54 IS - 12 N2 - PURPOSE: We previously showed that pre-exposure of the cornea to Toll-like receptor (TLR)5 ligand flagellin induces strong protective innate defense against microbial pathogens and hypothesized that flagellin modulates gene expression at the transcriptional levels. Thus, we sought to determine the role of one transcription factor, interferon regulatory factor (IRF1), and its target gene CXCL10 therein. METHODS: Superarray was used to identify transcription factors differentially expressed in Pseudomonas aeruginosa-challenged human corneal epithelial cells (CECs) with or without flagellin pretreatment. The expression of CXCL10, IRF1, LI-8(CXCL2), and IFNγ was determined by PCR, immunohistochemistry, Western/dot blotting, and/or ELISA. IRF1 knockout mice, CXCL10 and IFNγ neutralization, and NK cell depletion were used to define in vivo regulation and function of CXCL10. The severity of P. aeruginosa was assessed using clinical scoring, slit-lamp microscopy, bacterial counting, polymorphonuclear leukocytes (PMN) infiltration, and macrophage inflammatory protein 2/Chemokine (C-X-C motif) ligand 2 (MIP-2/CXCL2) expression. RESULTS: Flagellin pretreatment drastically affected P. aeruginosa-induced IRF1 expression in human CECs. However, flagellin pretreatment augmented the P. aeruginosa-induced expression of Irf1 and its target gene Cxcl10 in B6 mouse corneas. Irf1 deficiency reduced infection-triggered CXCL10 expression, increased keratitis severity, and attenuated flagellin-elicited protection compared to values in wild-type (WT) controls. CXCL10 neutralization in the cornea of WT mice displayed pathogenesis similar to that of IRF1⁻/⁻ mice. IFNγ receptor neutralization and NK cell depletion prevented flagellin-augmented IRF1 and CXCL10 expression and increased the susceptibility to P. aeruginosa infection in mouse corneas. CONCLUSIONS: IRF1 plays a role in the corneal innate immune response by regulating CXCL10 expression. IFNγ-producing NK cells augment the epithelial expression of IRF1 and CXCL10 and thus contribute to the innate defense of the cornea against P. aeruginosa infection. SN - 1552-5783 UR - https://www.unboundmedicine.com/medline/citation/24130180/Interferon_regulatory_factor_1_in_flagellin_induced_reprogramming:_potential_protective_role_of_CXCL10_in_cornea_innate_defense_against_Pseudomonas_aeruginosa_infection_ L2 - http://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.13-12453 DB - PRIME DP - Unbound Medicine ER -