4.4 Article

TLR9 agonist suppresses choroidal neovascularization by restricting endothelial cell motility via ERK/c-Jun pathway

Journal

MICROVASCULAR RESEARCH
Volume 141, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mvr.2022.104338

Keywords

Choroidal neovascularization; CpG-ODN; TLR9 agonist; Cell proliferation

Funding

  1. National Natural Science Foundation of China [81900868]
  2. Chongqing Education Commission Project of China [KJQN202001314]
  3. Scientific Research Foundation of the Chongqing University of Arts and Sciences [R2020FYX07]
  4. China Postdoctoral Science Foundation [2021M693753]

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This study demonstrates that CpG-ODN suppresses endothelial cell motility by restricting cell cycle progression at the G0/G1 phase. This effect is achieved through interaction with the ERK/c-Jun signaling pathway.
Introduction: Choroidal neovascularization (CNV) is the feature of neovascular age-related macular degeneration (AMD). It has been demonstrated that inflammation plays a key role in the development of CNV. Here we aim to investigate how TLR9 agonist (CpG-ODN), one of the key regulators of inflammatory responses, suppresses CNV in vivo. Materials and methods: The cell viability was assessed by MTT and EdU test after CpG-ODN treatment. Endothelial cells gap assay, tube formation assay and transwell assay were practiced to observe how CpG-ODN affected the endothelial cells functions. The choroidal explants and laser-induced CNV model were built to investigate how CpG-ODN suppressed angiogenesis. The ERK and c-Jun expression were evaluated to assess if CpG-ODN affected cell proliferation. Flow cytometry and qPCR was practiced to observe how CpG-ODN regulated cell proliferation. Results: Our data showed that CpG-ODN not only reduced CNV area in vivo, but also decreased the RPE damage. CpG-ODN inhibited endothelial cells from migration and forming tubes, while the effect was not toxic. EdU test and MTT test suggested that CpG-ODN inhibited endothelial cells proliferation. CpG-ODN significantly increased protein expression of phosphorylated c-Jun but reduced phosphorylated ERK in HUVECs, which was confirmed in ERK transfected 293T cells. JNK inhibitor abolished the suppression of endothelial cells migration and tube formation by CpG-ODN. The findings were also in agreement with the observation in CpG-ODN treated CNV eyes in vivo. The flow cytometry and qPCR data revealed that the suppression of cell motility by CpG-ODN was achieved by arresting endothelial cells cell cycle at G0/G1 phase. Conclusions: Our study demonstrated that CpG-ODN suppressed endothelial cell motility by restricting the cell cycle progression at G0/G1 phase, the effect of which was achieved by interacting with ERK/c-Jun pathways.

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