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Publications

Journal Article Epublish

PubMed: 40521204 DOI: 10.7150/thno.110322

Toll-like receptor 2 deficiency exacerbates corneal angiogenesis in injury by impairing regulatory T cells.

Theranostics 15(13):6082-6099

Authors: Jung Hwa Ko, Hyun Ju Lee, Hyeon Ji Kim, Jin Suk Ryu, Yoo Rim Choi, Chang Ho Yoon, Hyun Beom Song, Donghyun Kim, Ryang Hwa Lee, Joo Youn Oh

Affiliations

  • Laboratory of Ocular Regenerative Medicine and Immunology, Seoul National University Hospital Biomedical Research Institute, Seoul, Korea.
  • Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea.
  • Department of Tropical Medicine and Parasitology and Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
  • Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.
  • Department of Cell Biology and Genetics, Institute for Regenerative Medicine, Texas A&M University School of Medicine, College Station, TX, USA.
  • Laboratory of Ocular Regenerative Medicine and Immunology, Seoul National University Hospital Biomedical Research Institute, Seoul, Korea. Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea.

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.

MeSH

Toll-Like Receptors, Cells, T-Lymphocytes, Regulatory, Nanomedicine, Monocytes, Toll-Like Receptor 2, Homeostasis, Corneal Neovascularization, Endothelial Cells, Angiogenesis