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Theranostics, Published 2025-5-7, 15 (13) | https://doi.org/10.7150/thno.110322
Toll-like receptor 2 deficiency exacerbates corneal angiogenesis in injury by impairing regulatory T cells
Jung Hwa Ko1, Hyun Ju Lee1, Hyeon Ji Kim1, Jin Suk Ryu1, Yoo Rim Choi1, Chang Ho Yoon1,2, Hyun Beom Song3,4, Donghyun Kim4,5, Ryang Hwa Lee6, Joo Youn Oh1,2
1Laboratory of Ocular Regenerative Medicine and Immunology, Seoul National University Hospital Biomedical Research Institute, Seoul, Korea
2Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea
3Department of Tropical Medicine and Parasitology and Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea
4Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
5Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea
6Department of Cell Biology and Genetics, Institute for Regenerative Medicine, Texas A&M University School of Medicine, College Station, TX, USA
Corresponding author: Joo Youn Oh
1Laboratory of Ocular Regenerative Medicine and Immunology, Seoul National University Hospital Biomedical Research Institute, Seoul, Korea
2Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea
3Department of Tropical Medicine and Parasitology and Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea
4Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
5Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea
6Department of Cell Biology and Genetics, Institute for Regenerative Medicine, Texas A&M University School of Medicine, College Station, TX, USA
Corresponding author: Joo Youn Oh
Abstract
Background: Toll-like receptor (TLR) 2 is a primary sensor of injury, and regulatory T cells (Tregs) are crucial mediators of tissue homeostasis. In this study, we aimed to investigate whether TLR2 is necessary for Treg-mediated restoration of corneal homeostasis following injury.
Methods: We evaluated inflammatory corneal neovascularization and the proportions of Tregs, along with pro-angiogenic, pro-inflammatory monocytes, using a suture-induced corneal angiogenesis model in mice that either lacked TLR2 or were subjected to temporary TLR2 inhibition. The roles of injury-induced Tregs in corneal angiogenesis were further verified in vivo through adoptive transfer and in vitro using cultures of vascular endothelial cells.
Results: Inflammatory corneal neovascularization was significantly more pronounced in TLR2 knockout mice compared to wild-type mice, while no differences were observed in TLR4 knockout mice. Temporary TLR2 inhibition also exacerbated corneal neovascularization, whereas TLR4 inhibition did not. Mechanistically, corneal injury induced an increase in Tregs in wild-type mice, which was absent in TLR2 knockout mice. Conversely, pro-angiogenic, pro-inflammatory monocytes were elevated in TLR2 knockout mice. Adoptive transfer of injury-induced Tregs from wild-type to TLR2 knockout mice reduced corneal neovascularization and decreased the number of monocytes. Functional assays demonstrated that Tregs from TLR2 knockout mice exhibited lower cell proliferation and IL-10 secretion, but increased IFN-γ secretion compared to Tregs from wild-type mice. Furthermore, TLR2 knockout Tregs were less effective at inducing apoptosis and suppressing pro-inflammatory activation and tube formation of vascular endothelial cells than their wild-type counterparts.
Conclusion: Our findings suggest an expanded role for TLR2 in promoting corneal angiogenic and immunologic homeostasis during injury by regulating Treg numbers and functions.
Methods: We evaluated inflammatory corneal neovascularization and the proportions of Tregs, along with pro-angiogenic, pro-inflammatory monocytes, using a suture-induced corneal angiogenesis model in mice that either lacked TLR2 or were subjected to temporary TLR2 inhibition. The roles of injury-induced Tregs in corneal angiogenesis were further verified in vivo through adoptive transfer and in vitro using cultures of vascular endothelial cells.
Results: Inflammatory corneal neovascularization was significantly more pronounced in TLR2 knockout mice compared to wild-type mice, while no differences were observed in TLR4 knockout mice. Temporary TLR2 inhibition also exacerbated corneal neovascularization, whereas TLR4 inhibition did not. Mechanistically, corneal injury induced an increase in Tregs in wild-type mice, which was absent in TLR2 knockout mice. Conversely, pro-angiogenic, pro-inflammatory monocytes were elevated in TLR2 knockout mice. Adoptive transfer of injury-induced Tregs from wild-type to TLR2 knockout mice reduced corneal neovascularization and decreased the number of monocytes. Functional assays demonstrated that Tregs from TLR2 knockout mice exhibited lower cell proliferation and IL-10 secretion, but increased IFN-γ secretion compared to Tregs from wild-type mice. Furthermore, TLR2 knockout Tregs were less effective at inducing apoptosis and suppressing pro-inflammatory activation and tube formation of vascular endothelial cells than their wild-type counterparts.
Conclusion: Our findings suggest an expanded role for TLR2 in promoting corneal angiogenic and immunologic homeostasis during injury by regulating Treg numbers and functions.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-06-17)
- 국내(교신)+국외 연구진
- 의약학 > 응용의학
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