Shikonin alleviates choroidal neovascularization by inhibiting proangiogenic factor production from infiltrating macrophages

Ying Wang; Laiqing Xie; Manhui Zhu; Yang Guo; Yuanyuan Tu; Yamei Zhou; Jia Zeng; Linling Zhu; Shu Du; Zhenzhen Wang; Yuting Zhang; Xiaojuan Liu; E Song

doi:10.1016/j.exer.2021.108823

Shikonin alleviates choroidal neovascularization by inhibiting proangiogenic factor production from infiltrating macrophages

Exp Eye Res. 2021 Dec:213:108823. doi: 10.1016/j.exer.2021.108823. Epub 2021 Nov 6.

Authors

Ying Wang¹, Laiqing Xie², Manhui Zhu³, Yang Guo², Yuanyuan Tu³, Yamei Zhou⁴, Jia Zeng⁴, Linling Zhu³, Shu Du³, Zhenzhen Wang³, Yuting Zhang³, Xiaojuan Liu⁵, E Song⁶

Affiliations

¹ Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China; Department of Ophthalmology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
² Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
³ Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China.
⁴ Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, China.
⁵ Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, China. Electronic address: lxj@ntu.edu.cn.
⁶ Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: songe@suda.edu.cn.

PMID: 34752817
DOI: 10.1016/j.exer.2021.108823

Abstract

Choroidal neovascularization (CNV), a feature of neovasular age-related macular degeneration (AMD), acts as a leading cause of vision loss in the elderly. Shikonin (SHI), a natural bioactive compound extracted from Chinese herb radix arnebiae, exerts anti-inflammatory and anti-angiogenic roles and also acts as a potential pyruvate kinase M2 (PKM2) inhibitor in macrophages. The major immune cells macrophages infiltrate the CNV lesions, where the production of pro-angiognic cytokines from macrophage facilitates the development of CNV. PKM2 contributes to the neovascular diseases. In this study, we found that SHI oral gavage alleviated the leakage, area and volume of mouse laser-induced CNV lesion and inhibited macrophage infiltration without ocular cytotoxicity. Moreover, SHI inhibited the secretion of pro-angiogenic cytokine, including basic fibroblast growth factor (FGF2), insulin-like growth factor-1 (IGF1), chemokine (C-C motif) ligand 2 (CCL2), placental growth factor and vascular endothelial growth factor (VEGF), from primary human macrophages by down-regulating PKM2/STAT3/CD163 pathway, indicating a novel potential therapy strategy for CNV.

Keywords: Choroidal neovascularization (CNV); Macrophage; Pyruvate kinase M2 (PKM2); Shikonin (SHI).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inducing Agents / metabolism
Angiogenesis Inhibitors / therapeutic use*
Animals
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
Antigens, CD / metabolism
Antigens, Differentiation, Myelomonocytic / metabolism
Blotting, Western
Cells, Cultured
Choroidal Neovascularization / drug therapy*
Choroidal Neovascularization / enzymology
Chromatography, High Pressure Liquid
Coloring Agents / administration & dosage
Cytokines / metabolism
Disease Models, Animal
Drugs, Chinese Herbal / therapeutic use
Enzyme-Linked Immunosorbent Assay
Fluorescein Angiography
Humans
In Situ Nick-End Labeling
Indocyanine Green / administration & dosage
Macrophages / drug effects*
Macrophages / enzymology
Male
Mice
Mice, Inbred C57BL
Naphthoquinones / therapeutic use*
Phosphorylation
Pyruvate Kinase / antagonists & inhibitors*
Pyruvate Kinase / metabolism
Receptors, Cell Surface / antagonists & inhibitors
Receptors, Cell Surface / metabolism
STAT3 Transcription Factor / antagonists & inhibitors
STAT3 Transcription Factor / metabolism

Substances

Angiogenesis Inducing Agents
Angiogenesis Inhibitors
Anti-Inflammatory Agents, Non-Steroidal
Antigens, CD
Antigens, Differentiation, Myelomonocytic
CD163 antigen
Coloring Agents
Cytokines
Drugs, Chinese Herbal
Naphthoquinones
Receptors, Cell Surface
STAT3 Transcription Factor
Stat3 protein, mouse
shikonin
Pkm protein, mouse
Pyruvate Kinase
Indocyanine Green