TLR2/4 deficiency prevents oxygen-induced vascular degeneration and promotes revascularization by downregulating IL-17 in the retina.
Vascular degeneration is a critical pathological process in many human degenerative diseases, which need efficient ways to revascularization. However, little is known about cellular and molecular mechanisms that are used during vascular degeneration and revascularization. Here, we show that Toll-like receptor 2 and 4 (TLR2/4) double deficiency suppressed hyperoxia induced retinal vessel regression in an oxygen-induced retinopathy (OIR) model. Notably, the TLR2/4-/- mice experienced more revascularization after reduced vessel regression compared with wild-type mice, accompanied with less activation of glial cells. Mechanistically, TLR2/4 activation can tip the balance between Th17 cells and regulatory T cells towards Th17 cells, a critical source of the IL-17A. Less migration and infiltration of IL-17A-expressing proinflammatory cells but elevated regulatory T cells were observed in OIR-retinae from TLR2/4-/- mice. Coincidentally, TLR2/4 deficiency suppressed IL-17A production and increased expressions of anti-inflammatory genes. Furthermore, IL-17A promoted activation of glial cells. IL-17A blockade using a neutralizing antibody alleviated retinal cell apoptosis and glial activation in C57/B6-OIR mice, demonstrating the important role of IL-17A pathway in glial function during revascularization. Thus TLR2/4-mediated IL-17A inflammatory signaling is involved in vessel degeneration and revascularization, indicating that modulation of the TLR2/4-IL-17A pathway may be a novel therapeutic strategy for degenerative diseases.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, P. R. China.
Chang
C
He
Department of Haematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P. R. China.
Peilong
P
Lai
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, P. R. China.
Jing
J
Wang
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, P. R. China.
Tian
T
Zhou
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, P. R. China.
Zijing
Z
Huang
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, P. R. China.
Lingli
L
Zhou
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, P. R. China.
Xialin
X
Liu
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D009457:Neuroglia / Q000473:pathology; D010100:Oxygen / Q000009:adverse effects*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000378:metabolism
D020381:Interleukin-17; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D010100:Oxygen