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Frontiers in immunology2022; 13; 830871; doi: 10.3389/fimmu.2022.830871

Ex Vivo and In Vitro Analysis Identify a Detrimental Impact of Neutrophil Extracellular Traps on Eye Structures in Equine Recurrent Uveitis.

Abstract: Equine recurrent uveitis (ERU) is a common ocular disease of horses and described as a model for human autoimmune uveitis. This immune-mediated, inflammatory condition progressively destroys the eye, ultimately leading to blindness. Genetic and autoimmune factors, next to infections with Leptospira, are discussed as key factors in the pathogenesis. Furthermore, a release of neutrophil extracellular traps (NETs) by activated neutrophils is involved. NETs are composed of decondensed chromatin and proteins that can immobilize invading pathogens. However, if NETs accumulate, they can contribute to detrimental autoimmune processes. Thus, we aimed to investigate the impact of NETs in ERU patients. Therefore, we quantified several NET-markers (cell-free DNA, nucleosomes, citrullinated histone H3, histone-myeloperoxidase complexes, interleukin-17, equine cathelicidin 1 and DNase I activity) and NET-autoantibodies in sera and vitreous body fluids (VBF) of ERU-diseased horses and correlated the data with the disease status (signalment, ERU scores and Leptospira infection status). NET markers were detected to varying degrees in VBF of diseased horses, and partially correlated to disease severity and the presence of Leptospira spp. Cell-free DNA and nucleosomes as NET markers correlate with ERU severity in total and VBF scores, despite the presence of active DNases. Additionally, a significant correlation between fundus affection in the eye and NET autoantibodies was detectable. Therefore, we further investigated the influence of VBF samples from equine patients and isolated NETs on the blood-retina barrier in a cell culture model. VBF of diseased horses significantly induced cytotoxicity in retinal pigment epithelial cells. Moreover, partially digested NETs also resulted in cytotoxic effects. In the presence of lipopolysaccharide (LPS), the main component of the leptospiral surface, both undigested and completely digested NETs were cytotoxic. Correlations between the ERU-scores and Leptospira were also calculated. Detection of leptospiral DNA, and antibody titers of the serovar Grippotyphosa correlated with disease severity. In addition, a correlation between Leptospira and several NET markers was observed in VBF. Altogether, our findings suggest a positive correlation between NET markers with disease severity and involvement of Leptospira in the VBF of ERU-diseased horses, as well as a cytotoxic effect of NETs in eyes.
Copyright © 2022 Fingerhut, Yücel, Strutzberg-Minder, von Köckritz-Blickwede, Ohnesorge and de Buhr.
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Publication Date: 2022-02-10 PubMed ID: 35251020PubMed Central: PMC8896353DOI: 10.3389/fimmu.2022.830871Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Equine recurrent uveitis (ERU) is a frequent eye disease in horses, with detrimental effects including blindness. This study examined the role of neutrophil extracellular traps (NETs) in worsening ERU’s impact, finding that NETs have a toxic effect on eye structure and increases ERU’s severity and progression. Furthermore, it was found that bacterial infection heightens NETs’ negative effects on ERU.

Background of the Study

  • ERU is an inflammation of the eyes that results from an immune disorder and can progress to blindness. It’s widespread in horses and serves as a comparable model for autoimmune uveitis in humans.
  • Genetic elements, autoimmune responses, and infections (specifically Leptospira) are considered significant causes of ERU.
  • NETs, produced by active neutrophils, are comprised of decondensed chromatin and proteins, functioning as a defense mechanism to capture invading pathogens. However, excess accumulation of NETs can lead to detrimental autoimmune reactions, which is why this research aimed to study the impact of NETs on ERU patients.

Methods of the Study

  • Researchers measureed various NET-markers and NET-autoantibodies in the blood and intraocular fluids (Vitreous Body Fluids, VBF) of horses suffering from ERU.
  • This data was then correlated with the state of the disease in each horse.
  • Furthermore, the study explored the effects of VBF from ERU affected horses on the blood-retina barrier using a cell culture model.

Findings of the Study

  • The analysis indicated varying degrees of NET markers in the VBF of diseased horses. These markers partly correlated to disease severity and the presence of Leptospira.
  • Cell-free DNA and nucleosomes, indicators of NETs, were found to correlate with ERU severity despite the presence of active DNases.
  • Additionally, the research pinpointed a direct association between the extent of damage in the eye (fundus affection) and the presence of NET autoantibodies.
  • The presence of Leptospiral DNA and Grippotyphosa serovar antibodies was found to directly correlate with disease severity.
  • NETs and their markers were observed to be cytotoxic to retinal pigment epithelial cells, both when isolated and when present in VBF.
  • A correlation between ERU disease severity and levels of Leptospira was also seen.

Conclusion of the Study

  • The study concludes a strong correlation between NET markers and severity of ERU. This suggests that NETs contribute to the worsening of ERU, especially when associated with infection by Leptospira.
  • It also indicates that NETs may have a cytotoxic effect on the structures of the eye, potentially contributing to progressive blindness.

Cite This Article

APA
Fingerhut L, Yücel L, Strutzberg-Minder K, von Köckritz-Blickwede M, Ohnesorge B, de Buhr N. (2022). Ex Vivo and In Vitro Analysis Identify a Detrimental Impact of Neutrophil Extracellular Traps on Eye Structures in Equine Recurrent Uveitis. Front Immunol, 13, 830871. https://doi.org/10.3389/fimmu.2022.830871

Publication

Frontiers in immunology
ISSN: 1664-3224
NlmUniqueID: 101560960
Country: Switzerland
Language: English
Volume: 13
Pages: 830871

Researcher Affiliations

Fingerhut, Leonie
  • Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
  • Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
  • Clinic for Horses, University of Veterinary Medicine Hannover, Hannover, Germany.
Yücel, Leyla
  • Clinic for Horses, University of Veterinary Medicine Hannover, Hannover, Germany.
  • Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.
Strutzberg-Minder, Katrin
  • IVD Innovative Veterinary Diagnostics (IVD GmbH), Seelze, Germany.
von Köckritz-Blickwede, Maren
  • Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
  • Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
Ohnesorge, Bernhard
  • Clinic for Horses, University of Veterinary Medicine Hannover, Hannover, Germany.
de Buhr, Nicole
  • Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
  • Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.

MeSH Terms

  • Animals
  • Autoantibodies
  • Biomarkers
  • Cell-Free Nucleic Acids
  • Chronic Disease
  • Extracellular Traps
  • Histones
  • Horse Diseases / diagnosis
  • Horses
  • Leptospira
  • Nucleosomes
  • Uveitis / veterinary

Conflict of Interest Statement

Author KS-M is employed by IVD Innovative Veterinary Diagnostics (IVD GmbH), Seelze, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Citations

This article has been cited 8 times.
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