TLR9 ligand CpG-ODN applied to the injured mouse cornea elicits retinal inflammation

Holly R Chinnery, Samuel McLenachan, Nicolette Binz, Yan Sun, John V Forrester, Mariapia A Degli-Esposti, Eric Pearlman, Paul G McMenamin

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

During bacterial and viral infections, unmethylated CpG-DNA released by proliferating and dying microbes is recognized by toll-like receptor (TLR) 9 in host cells, initiating innate immune responses. Many corneal infections occur secondary to epithelial breaches and represent a major cause of vision impairment and blindness globally. To mimic this clinical situation, we investigated mechanisms of TLR9 ligand-induced corneal inflammation in mice after epithelial debridement. Application of CpG oligodeoxynucleotides (ODNs) resulted in neutrophil and macrophage infiltration to the cornea and loss of transparency. By 6 hours after CpG-ODN administration, TLR9 mRNA was increased in the cornea and retina. In vivo clinical examination at 24 hours revealed inflammatory infiltrates in the vitreous and retina, which were confirmed ex vivo to be neutrophils and macrophages, along with activated resident microglia. CpG-ODN-induced intraocular inflammation was abrogated in TLR9(-/-) and macrophage-depleted mice. Bone marrow reconstitution of irradiated TLR9(-/-) mice with TLR9(+/+) bone marrow led to restored corneal inflammatory responses to CpG-ODN. Fluorescein isothiocyanate-CpG-ODN rapidly penetrated the cornea and ocular media to reach the retina, where it was present within CD68(+) retinal macrophages and microglia. These data show that topically applied CpG-ODN induces intraocular inflammation owing to TLR9 activation of monocyte-lineage cells. These novel findings indicate that microbial CpG-DNA released during bacterial and/or viral keratitis can cause widespread inflammation within the eye, including the retina.
Original languageEnglish
Pages (from-to)209-220
Number of pages12
JournalAmerican Journal of Pathology
Volume180
Issue number1
Early online date12 Nov 2011
DOIs
Publication statusPublished - Jan 2012

Fingerprint

Oligodeoxyribonucleotides
Cornea
Ligands
Inflammation
Retina
Macrophages
Microglia
Bone Marrow
Toll-Like Receptor 9
Neutrophil Infiltration
Keratitis
DNA
Virus Diseases
Debridement
Blindness
Fluorescein
Coinfection
Bacterial Infections
Innate Immunity
Monocytes

Keywords

  • Adjuvants, Immunologic
  • Animals
  • Cornea
  • Immunity, Innate
  • Keratitis
  • Lipopolysaccharides
  • Macrophages
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neutrophil Infiltration
  • Oligodeoxyribonucleotides
  • Retinitis
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9

Cite this

Chinnery, H. R., McLenachan, S., Binz, N., Sun, Y., Forrester, J. V., Degli-Esposti, M. A., ... McMenamin, P. G. (2012). TLR9 ligand CpG-ODN applied to the injured mouse cornea elicits retinal inflammation. American Journal of Pathology, 180(1), 209-220. https://doi.org/10.1016/j.ajpath.2011.09.041

TLR9 ligand CpG-ODN applied to the injured mouse cornea elicits retinal inflammation. / Chinnery, Holly R; McLenachan, Samuel; Binz, Nicolette; Sun, Yan; Forrester, John V; Degli-Esposti, Mariapia A; Pearlman, Eric; McMenamin, Paul G.

In: American Journal of Pathology, Vol. 180, No. 1, 01.2012, p. 209-220.

Research output: Contribution to journalArticle

Chinnery, HR, McLenachan, S, Binz, N, Sun, Y, Forrester, JV, Degli-Esposti, MA, Pearlman, E & McMenamin, PG 2012, 'TLR9 ligand CpG-ODN applied to the injured mouse cornea elicits retinal inflammation', American Journal of Pathology, vol. 180, no. 1, pp. 209-220. https://doi.org/10.1016/j.ajpath.2011.09.041
Chinnery HR, McLenachan S, Binz N, Sun Y, Forrester JV, Degli-Esposti MA et al. TLR9 ligand CpG-ODN applied to the injured mouse cornea elicits retinal inflammation. American Journal of Pathology. 2012 Jan;180(1):209-220. https://doi.org/10.1016/j.ajpath.2011.09.041
Chinnery, Holly R ; McLenachan, Samuel ; Binz, Nicolette ; Sun, Yan ; Forrester, John V ; Degli-Esposti, Mariapia A ; Pearlman, Eric ; McMenamin, Paul G. / TLR9 ligand CpG-ODN applied to the injured mouse cornea elicits retinal inflammation. In: American Journal of Pathology. 2012 ; Vol. 180, No. 1. pp. 209-220.
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abstract = "During bacterial and viral infections, unmethylated CpG-DNA released by proliferating and dying microbes is recognized by toll-like receptor (TLR) 9 in host cells, initiating innate immune responses. Many corneal infections occur secondary to epithelial breaches and represent a major cause of vision impairment and blindness globally. To mimic this clinical situation, we investigated mechanisms of TLR9 ligand-induced corneal inflammation in mice after epithelial debridement. Application of CpG oligodeoxynucleotides (ODNs) resulted in neutrophil and macrophage infiltration to the cornea and loss of transparency. By 6 hours after CpG-ODN administration, TLR9 mRNA was increased in the cornea and retina. In vivo clinical examination at 24 hours revealed inflammatory infiltrates in the vitreous and retina, which were confirmed ex vivo to be neutrophils and macrophages, along with activated resident microglia. CpG-ODN-induced intraocular inflammation was abrogated in TLR9(-/-) and macrophage-depleted mice. Bone marrow reconstitution of irradiated TLR9(-/-) mice with TLR9(+/+) bone marrow led to restored corneal inflammatory responses to CpG-ODN. Fluorescein isothiocyanate-CpG-ODN rapidly penetrated the cornea and ocular media to reach the retina, where it was present within CD68(+) retinal macrophages and microglia. These data show that topically applied CpG-ODN induces intraocular inflammation owing to TLR9 activation of monocyte-lineage cells. These novel findings indicate that microbial CpG-DNA released during bacterial and/or viral keratitis can cause widespread inflammation within the eye, including the retina.",
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AU - Sun, Yan

AU - Forrester, John V

AU - Degli-Esposti, Mariapia A

AU - Pearlman, Eric

AU - McMenamin, Paul G

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N2 - During bacterial and viral infections, unmethylated CpG-DNA released by proliferating and dying microbes is recognized by toll-like receptor (TLR) 9 in host cells, initiating innate immune responses. Many corneal infections occur secondary to epithelial breaches and represent a major cause of vision impairment and blindness globally. To mimic this clinical situation, we investigated mechanisms of TLR9 ligand-induced corneal inflammation in mice after epithelial debridement. Application of CpG oligodeoxynucleotides (ODNs) resulted in neutrophil and macrophage infiltration to the cornea and loss of transparency. By 6 hours after CpG-ODN administration, TLR9 mRNA was increased in the cornea and retina. In vivo clinical examination at 24 hours revealed inflammatory infiltrates in the vitreous and retina, which were confirmed ex vivo to be neutrophils and macrophages, along with activated resident microglia. CpG-ODN-induced intraocular inflammation was abrogated in TLR9(-/-) and macrophage-depleted mice. Bone marrow reconstitution of irradiated TLR9(-/-) mice with TLR9(+/+) bone marrow led to restored corneal inflammatory responses to CpG-ODN. Fluorescein isothiocyanate-CpG-ODN rapidly penetrated the cornea and ocular media to reach the retina, where it was present within CD68(+) retinal macrophages and microglia. These data show that topically applied CpG-ODN induces intraocular inflammation owing to TLR9 activation of monocyte-lineage cells. These novel findings indicate that microbial CpG-DNA released during bacterial and/or viral keratitis can cause widespread inflammation within the eye, including the retina.

AB - During bacterial and viral infections, unmethylated CpG-DNA released by proliferating and dying microbes is recognized by toll-like receptor (TLR) 9 in host cells, initiating innate immune responses. Many corneal infections occur secondary to epithelial breaches and represent a major cause of vision impairment and blindness globally. To mimic this clinical situation, we investigated mechanisms of TLR9 ligand-induced corneal inflammation in mice after epithelial debridement. Application of CpG oligodeoxynucleotides (ODNs) resulted in neutrophil and macrophage infiltration to the cornea and loss of transparency. By 6 hours after CpG-ODN administration, TLR9 mRNA was increased in the cornea and retina. In vivo clinical examination at 24 hours revealed inflammatory infiltrates in the vitreous and retina, which were confirmed ex vivo to be neutrophils and macrophages, along with activated resident microglia. CpG-ODN-induced intraocular inflammation was abrogated in TLR9(-/-) and macrophage-depleted mice. Bone marrow reconstitution of irradiated TLR9(-/-) mice with TLR9(+/+) bone marrow led to restored corneal inflammatory responses to CpG-ODN. Fluorescein isothiocyanate-CpG-ODN rapidly penetrated the cornea and ocular media to reach the retina, where it was present within CD68(+) retinal macrophages and microglia. These data show that topically applied CpG-ODN induces intraocular inflammation owing to TLR9 activation of monocyte-lineage cells. These novel findings indicate that microbial CpG-DNA released during bacterial and/or viral keratitis can cause widespread inflammation within the eye, including the retina.

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KW - Mice, Inbred C57BL

KW - Neutrophil Infiltration

KW - Oligodeoxyribonucleotides

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