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Murine Corneal Transplantation: A Model to Study the Most Common Form of Solid Organ Transplantation
Published on: November 17, 2014
The Necroptosis Pathway Is Upregulated in the Cornea in Mice With Ocular Graft-Versus-Host Disease
Kazuki Asai1, Hyung Keun Lee2, Shinri Sato1
1Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Purpose:
To identify molecular signatures specific for ocular graft-versus-host disease (GVHD) by proteomic analysis of corneas from mice with GVHD.
Methods:
We identified differentially expressed proteins (DEPs) in corneal samples from GVHD model mice and syngeneic control mice 4 weeks after bone marrow transplantation. Data-independent acquisition analysis was performed on individual samples, and the roles of DEPs in biological pathways related to GVHD were evaluated via bioinformatics and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses.
Results:
Three important signaling pathways were upregulated in the cornea in mice with GVHD: (1) the necroptosis pathway, (2) the mitogen-activated protein kinase (MAPK) pathway, and (3) as previously reported, the neutrophil extracellular trap (NET) pathway. In those signaling pathways, we identified new upregulated molecules, including (1) receptor-interacting protein kinase 1 (RIPK1), RIPK3, interferon regulatory factor 9, the interferon-induced double-stranded RNA-activated protein kinase lipoxygenase, and high mobility group box1 (HMGB1) which are damage-associated molecular patterns (DAMPs) in the necroptosis pathway; (2) the sequentially upregulated interleukin 1 (IL-1) receptor-associated kinase (IRAK), an evolutionarily conserved signaling intermediate in the Toll pathway (ECSIT), and p38, which is downstream of the IL-1 receptor and increased CDC42/Rac (Rac2), a Rho family GTPase in the MAPK pathway; and (3) the integrin components CR3 and macrophage-1 antigen (MAC-1), which are DAMPs, and the pyroptosis-related protein gasdermin D (GSDMD) in the NET pathway.
Conclusions:
These novel molecules may help researchers elucidate the pathogenesis of GVHD and identify new therapeutic targets for corneal changes in patients with ocular GVHD.
Insights
Researchers identified key molecular signatures in mouse corneas with ocular graft-versus-host disease (GVHD). This proteomic analysis revealed upregulated pathways and novel molecules, offering potential therapeutic targets for GVHD-related corneal complications.
Area of Science:
- Ophthalmology
- Immunology
- Proteomics
Background:
- Ocular graft-versus-host disease (GVHD) is a significant complication following allogeneic stem cell transplantation.
- Understanding the molecular mechanisms underlying corneal involvement in GVHD is crucial for developing effective treatments.
Purpose of the Study:
- To identify specific molecular signatures in the cornea associated with ocular GVHD using proteomic analysis.
- To elucidate the biological pathways and novel molecules involved in the pathogenesis of corneal GVHD.
Main Methods:
- Proteomic analysis of corneal samples from a murine GVHD model and syngeneic controls.
- Data-independent acquisition mass spectrometry was employed for protein identification and quantification.
- Bioinformatics and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to evaluate the functional roles of differentially expressed proteins (DEPs).
Main Results:
- Three key signaling pathways were found to be upregulated in the cornea during GVHD: necroptosis, mitogen-activated protein kinase (MAPK), and neutrophil extracellular trap (NET) pathways.
- Novel upregulated molecules were identified within these pathways, including receptor-interacting protein kinase 1 (RIPK1), RIPK3, high mobility group box1 (HMGB1), interleukin-1 receptor-associated kinase (IRAK), and gasdermin D (GSDMD).
- These identified molecules include damage-associated molecular patterns (DAMPs) and components of inflammatory signaling cascades.
Conclusions:
- The identified novel molecules represent potential biomarkers for ocular GVHD.
- These findings contribute to a deeper understanding of the pathogenesis of GVHD in the cornea.
- The novel molecules may serve as potential therapeutic targets for managing corneal complications in patients with ocular GVHD.
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