The phase changes of M1/M2 phenotype of microglia/macrophage following oxygen-induced retinopathy in mice

• Published in: Inflammation research Vol. 70; no. 2; pp. 183 - 192
• Main Authors: Li, Jia, Yu, Shanshan, Lu, Xi, Cui, Kaixuan, Tang, Xiaoyu, Xu, Yue, Liang, Xiaoling
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2021; Springer Nature B.V
• Subjects: Age; Age related diseases; Allergology; Animals; Biomedical and Life Sciences; Biomedicine; Cell activation; Cytokines; Cytokines - immunology; Dermatology; Diabetes mellitus; Diabetic retinopathy; Eye diseases; Genotype & phenotype; Hyperoxia; IL-1β; Immunology; Inflammation; Interleukin 4; Interleukin 6; Macrophages; Macrophages - immunology; Macular degeneration; Mice; Mice, Inbred C57BL; Microglia; Microglia - immunology; Neurology; NF-kappa B - immunology; NF-κB protein; Original Research Paper; Oxygen; Peroxisome proliferator-activated receptors; Pharmacology/Toxicology; Phenotype; Phenotypes; Polarization; Polymerase chain reaction; PPAR gamma - immunology; Regression analysis; Regulatory mechanisms (biology); Retina; Retina - immunology; Retinal Diseases - immunology; Retinopathy; Rheumatology; Signal Transduction; Signaling; Stat3 protein; STAT3 Transcription Factor - immunology; Stat6 protein; STAT6 Transcription Factor - immunology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vascularization; Microglia/macrophage polarization; Inflammation cytokines; Retinal neovascularization; Oxygen-induced retinopathy
• ISSN: 1023-3830; 1420-908X; 1420-908X
• DOI: 10.1007/s00011-020-01427-w

Objective Microglia/macrophage activation is previously reported to be involved in various ocular diseases. However, the separate role of M1/M2 phenotype microglia/macrophage in the pathological process of oxygen-induced retinopathy (OIR) remains unknown. In this research, we explored the role and regulatory mechanism of M1/M2 microglia/macrophage in OIR in C57BL/6J mice. Furthermore, we demonstrated the time phase of M1/M2 shifting of microglia/macrophage during the natural process of OIR, which is very essential for further investigations. Materials and methods C57BL/6j pups were exposed to hyperoxia environment from postnatal 7(P7) to P12 then returned to normoxia. The mice were then euthanized, and the eyes were harvested at a series of time points for further investigation. The M1/M2 phenotype microglia/macrophage activity was presented by immunofluorescent staining and real-time quantitative polymerase chain reaction (qPCR). The NF-κb-STAT3 signaling and IL-4-STAT6-PPAR-γ signaling pathway activity was examined by western blot analysis. Results The microglia/macrophage were activated when the OIR model was set up after P12. The M1 microglia/macrophage activation was found in neovascularization (NV) tufts in both central and peripheral retina, which started from P12 when the mice were returned to normoxia environment and peaked at P17. During this period of time, the NF-κb-STAT3 signaling pathway was activated, resulting in the upregulated M1 phenotype microglia/macrophage polarization, along with the enhanced inflammatory cytokine expression including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β. Consequently, the NV tufts were observed from P12 and the volume continued to increase until P17. However, the M2 phenotype microglia/macrophage activity took over during the late phase of OIR started from P17. The IL-4-STAT6-PPAR-γ signaling activity was upregulated from P17 and peaked at P20, inducing M2 phenotype microglia polarization, which consequently led to the inhibition of inflammatory cytokines and spontaneous regression of NV tufts. Conclusions Microglia/macrophage participate actively in the natural process of OIR in mice, and two phenotypes exert different functions. Treatment modulating microglia/macrophage polarize toward M2 phenotype might be a novel and promising method for ocular neovascular diseases such as retinopathy of prematurity (ROP), wet age-related macular degeneration (wAMD), and diabetic retinopathy (DR).