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Inhibition of integrin ?5?1 ameliorates VEGF-induced retinal neovascularization
and leakage by suppressing NLRP3 inflammasome signaling in a mouse model
#MMPMID29502235
Sui A
; Zhong Y
; Demetriades AM
; Lu Q
; Cai Y
; Gao Y
; Zhu Y
; Shen X
; Xie B
Graefes Arch Clin Exp Ophthalmol
2018[May]; 256
(5
): 951-961
PMID29502235
show ga
PURPOSE: To assess the effect of inhibiting integrin ?5?1 by ATN-161 on vascular
endothelial growth factor (VEGF)-induced neovascularization (NV) and leakage
causing retinal detachment in adult Tet/opsin/VEGF transgenic mice, and
characterize the underlying mechanism of its function. METHOD: Retinas from adult
Tet/opsin/VEGF transgenic mice and human retinal endothelial cells (HRECs)
exposed to VEGF (treated with ATN-161 or PBS) were used to carry out
immunofluorescence, RT-PCR and western blot to examine expression levels of
integrin ?5?1 and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3)
inflammasome. Retinal frozen section analysis was used to assess NV and leakage
causing retinal detachment. RESULTS: In comparison to normal-treated mice,
doxycycline-treated Tet/opsin/VEGF transgenic mice showed severe retinal
detachment and higher integrin ?5?1 expression. Furthermore, the retinal
detachment was inhibited significantly by ATN-161. Additionally, ATN-161
treatment was associated with a conspicuous reduction in NLRP3,
apoptosis-associated speck-like protein containing a CARD (ASC), cleaved
caspase-1, and mature interleukin-1? expression levels in the retinas of
Tet/opsin/VEGF transgenic mice treated with doxycycline as well as in HRECs
exposed to VEGF. CONCLUSION: ATN-161, an antagonist of integrin ?5?1, is a
promising treatment for retinal neovascularization (RNV), and its retinal
protection role appears to take effect through inhibition of NLRP3 inflammasome
activity.
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