Galectin-8 Downmodulates TLR4 Activation and Impairs Bacterial Clearance in a Mouse Model of Pseudomonas aeruginosa Keratitis
(2023) In Journal of immunology 210(4). p.398-407- Abstract
- Pseudomonas aeruginosa provokes a painful, sight-threatening corneal infection. It progresses rapidly and is difficult to treat. In this study, using a mouse model of P. aeruginosa keratitis, we demonstrate the importance of a carbohydrate-binding protein, galectin-8 (Gal-8), in regulation of the innate immune response. First, using two distinct strains of P. aeruginosa, we established that Gal-8−/− mice are resistant to P. aeruginosa keratitis. In contrast, mice deficient in Gal-1, Gal-3, and Gal-9 were fully susceptible. Second, the addition of exogenous rGal-8 to LPS (TLR4 ligand)–stimulated bone marrow-derived macrophages suppressed 1) the activation of the NF-κB pathway, and 2) formation... (More)
- Pseudomonas aeruginosa provokes a painful, sight-threatening corneal infection. It progresses rapidly and is difficult to treat. In this study, using a mouse model of P. aeruginosa keratitis, we demonstrate the importance of a carbohydrate-binding protein, galectin-8 (Gal-8), in regulation of the innate immune response. First, using two distinct strains of P. aeruginosa, we established that Gal-8−/− mice are resistant to P. aeruginosa keratitis. In contrast, mice deficient in Gal-1, Gal-3, and Gal-9 were fully susceptible. Second, the addition of exogenous rGal-8 to LPS (TLR4 ligand)–stimulated bone marrow-derived macrophages suppressed 1) the activation of the NF-κB pathway, and 2) formation of the MD-2/TLR4 complex. Additionally, the expression level of reactive oxygen species was substantially higher in infected Gal-8−/− bone marrow neutrophils (BMNs) compared with the Gal-8+/+ BMNs, and the P. aeruginosa killing capacity of Gal-8−/− BMNs was considerably higher compared with that of Gal-8+/+ BMNs. In the bacterial killing assays, the addition of exogenous rGal-8 almost completely rescued the phenotype of Gal-8−/− BMNs. Finally, we demonstrate that a subconjunctival injection of a Gal-8 inhibitor markedly reduces the severity of infection in the mouse model of P. aeruginosa keratitis. These data lead us to conclude that Gal-8 downmodulates the innate immune response by suppressing activation of the TLR4 pathway and clearance of P. aeruginosa by neutrophils. These findings have broad implications for developing novel therapeutic strategies for treatment of conditions resulting from the hyperactive immune response both in ocular as well as nonocular tissues. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/a941ad13-535d-4526-abfb-950ce60bcb14
- author
- Ramadan, Abdulraouf ; Cao, Zhiyi ; Hassan, Mujtaba LU ; Zetterberg, Fredrik ; Nilsson, Ulf J. LU ; Gadjeva, Mihaela ; Rathinam, Vijay and Panjwani, Noorjahan
- organization
- publishing date
- 2023-02-15
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Animals, Mice, Pseudomonas aeruginosa, Toll-Like Receptor 4, Keratitis, Immunity, Innate, Galectins, Pseudomonas Infections, Mice, Inbred C57BL
- in
- Journal of immunology
- volume
- 210
- issue
- 4
- pages
- 10 pages
- publisher
- American Association of Immunologists
- external identifiers
-
- pmid:36603009
- scopus:85147318337
- ISSN
- 1550-6606
- DOI
- 10.4049/jimmunol.2200706
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2023 by The American Association of Immunologists, Inc.
- id
- a941ad13-535d-4526-abfb-950ce60bcb14
- date added to LUP
- 2023-02-07 08:45:33
- date last changed
- 2024-06-13 14:16:44
@article{a941ad13-535d-4526-abfb-950ce60bcb14,
abstract = {{<em>Pseudomonas aeruginosa</em> provokes a painful, sight-threatening corneal infection. It progresses rapidly and is difficult to treat. In this study, using a mouse model of <em>P. aeruginosa</em> keratitis, we demonstrate the importance of a carbohydrate-binding protein, galectin-8 (Gal-8), in regulation of the innate immune response. First, using two distinct strains of <em>P. aeruginosa</em>, we established that Gal-8<sup>−/−</sup> mice are resistant to <em>P. aeruginosa</em> keratitis. In contrast, mice deficient in Gal-1, Gal-3, and Gal-9 were fully susceptible. Second, the addition of exogenous rGal-8 to LPS (TLR4 ligand)–stimulated bone marrow-derived macrophages suppressed 1) the activation of the NF-κB pathway, and 2) formation of the MD-2/TLR4 complex. Additionally, the expression level of reactive oxygen species was substantially higher in infected Gal-8<sup>−/−</sup> bone marrow neutrophils (BMNs) compared with the Gal-8<sup>+/+</sup> BMNs, and the <em>P. aeruginosa</em> killing capacity of Gal-8<sup>−/−</sup> BMNs was considerably higher compared with that of Gal-8<sup>+/+</sup> BMNs. In the bacterial killing assays, the addition of exogenous rGal-8 almost completely rescued the phenotype of Gal-8<sup>−/−</sup> BMNs. Finally, we demonstrate that a subconjunctival injection of a Gal-8 inhibitor markedly reduces the severity of infection in the mouse model of <em>P. aeruginosa</em> keratitis. These data lead us to conclude that Gal-8 downmodulates the innate immune response by suppressing activation of the TLR4 pathway and clearance of <em>P. aeruginosa</em> by neutrophils. These findings have broad implications for developing novel therapeutic strategies for treatment of conditions resulting from the hyperactive immune response both in ocular as well as nonocular tissues.}},
author = {{Ramadan, Abdulraouf and Cao, Zhiyi and Hassan, Mujtaba and Zetterberg, Fredrik and Nilsson, Ulf J. and Gadjeva, Mihaela and Rathinam, Vijay and Panjwani, Noorjahan}},
issn = {{1550-6606}},
keywords = {{Animals; Mice; Pseudomonas aeruginosa; Toll-Like Receptor 4; Keratitis; Immunity, Innate; Galectins; Pseudomonas Infections; Mice, Inbred C57BL}},
language = {{eng}},
month = {{02}},
number = {{4}},
pages = {{398--407}},
publisher = {{American Association of Immunologists}},
series = {{Journal of immunology}},
title = {{Galectin-8 Downmodulates TLR4 Activation and Impairs Bacterial Clearance in a Mouse Model of <i>Pseudomonas aeruginosa </i>Keratitis}},
url = {{http://dx.doi.org/10.4049/jimmunol.2200706}},
doi = {{10.4049/jimmunol.2200706}},
volume = {{210}},
year = {{2023}},
}