Celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats

Zhanrong Li,1,* Jingguo Li,1,* Lei Zhu,1 Ying Zhang,1 Junjie Zhang,1 Lin Yao,2 Dan Liang,2 Liya Wang1 1Henan Eye Institute, Henan Eye Hospital, Henan Provincial People’s Hospital and Zhengzhou University People’s Hospital, Zhengzhou, 2State Key Laboratory of Ophthalmology, Zhong...

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Autores principales:	Li Z, Li J, Zhu L, Zhang Y, Zhang J, Yao L, Liang D, Wang L
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	celastrol nano-micelles macrophages corneal neovascularization Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/764bf14f9c9c432ca5d8239cfd60a216
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spelling	oai:doaj.org-article:764bf14f9c9c432ca5d8239cfd60a2162021-12-02T01:04:56ZCelastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats1178-2013https://doaj.org/article/764bf14f9c9c432ca5d8239cfd60a2162016-11-01T00:00:00Zhttps://www.dovepress.com/celastrol-nanomicelles-attenuate-cytokine-secretion-in-macrophages-and-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Zhanrong Li,1,* Jingguo Li,1,* Lei Zhu,1 Ying Zhang,1 Junjie Zhang,1 Lin Yao,2 Dan Liang,2 Liya Wang1 1Henan Eye Institute, Henan Eye Hospital, Henan Provincial People’s Hospital and Zhengzhou University People’s Hospital, Zhengzhou, 2State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: The aim of the present study was to investigate the inhibitory effects of celastrol-loaded nanomicelles (CNMs) on activated macrophage-induced corneal neovascularization (CNV) in rats and cytokine secretion in macrophages. Using an angiogenesis assay in vitro, we detected the effects of CNMs on human umbilical vein endothelial cell (HUVEC) migration and invasion. In addition, the expression levels of cytokines secreted from hypoxia-induced macrophages were assessed through cytokine array analysis. The expression of hypoxia-inducible factors-1α (HIF-1α), nuclear factor-kappa B p65 (NF-κB p65), phospho-nuclear factor-kappa B p65 (phospho-NF-κB p65), p38 mitogen-activated protein kinase (p38 MAPK), phospho-p38 MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2), and phospho-ERK1/2 was analyzed by western blotting. Activated macrophages were elicited through mineral oil lumbar injection, labeled with 1,19-dioctadecyl-3-3-39,39-tetramethylindocarbocyanine (DiI) and implanted into the corneal micro-pocket to induce CNV and to assess the antiangiogenic effect in rats. CNV was morphometrically analyzed using ImageJ software. Histopathological features were evaluated by immunofluorescence immunostaining for vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) on day 2 after surgery. In the present study, the results indicated that CNMs significantly inhibited the migration and invasion of HUVECs; remarkably attenuated the expression of VEGF, tumor necrosis factor-α, interleukin-1α, monocyte chemoattractant protein 1, cytokine-induced neutrophil chemoattractant 3, and MMP-9 protein; and downregulated ERK1/2, p38 MAPK, NF-κB activation, and HIF-1α expression in macrophages. The peritoneal cells elicited using mineral oil were highly purified macrophages, and the length and area of CNV were significantly decreased in the CNMs group compared with the control group. There was a significant reduction in the expression of VEGF and MMP-9 in activated macrophages and corneal tissue after pretreatment with CNMs in this model. In conclusion, CNMs potently suppressed macrophage-induced CNV via the inhibition of VEGF and MMP-9 expression. This effect might be mediated through attenuating macrophages via HIF-1α, MAPK, and NF-κB signaling pathways. Keywords: celastrol, nanomicelles, macrophages, corneal neovascularizationLi ZLi JZhu LZhang YZhang JYao LLiang DWang LDove Medical Pressarticlecelastrolnano-micellesmacrophagescorneal neovascularizationMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 11, Pp 6135-6148 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	celastrol nano-micelles macrophages corneal neovascularization Medicine (General) R5-920
spellingShingle	celastrol nano-micelles macrophages corneal neovascularization Medicine (General) R5-920 Li Z Li J Zhu L Zhang Y Zhang J Yao L Liang D Wang L Celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats
description	Zhanrong Li,1,* Jingguo Li,1,* Lei Zhu,1 Ying Zhang,1 Junjie Zhang,1 Lin Yao,2 Dan Liang,2 Liya Wang1 1Henan Eye Institute, Henan Eye Hospital, Henan Provincial People’s Hospital and Zhengzhou University People’s Hospital, Zhengzhou, 2State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: The aim of the present study was to investigate the inhibitory effects of celastrol-loaded nanomicelles (CNMs) on activated macrophage-induced corneal neovascularization (CNV) in rats and cytokine secretion in macrophages. Using an angiogenesis assay in vitro, we detected the effects of CNMs on human umbilical vein endothelial cell (HUVEC) migration and invasion. In addition, the expression levels of cytokines secreted from hypoxia-induced macrophages were assessed through cytokine array analysis. The expression of hypoxia-inducible factors-1α (HIF-1α), nuclear factor-kappa B p65 (NF-κB p65), phospho-nuclear factor-kappa B p65 (phospho-NF-κB p65), p38 mitogen-activated protein kinase (p38 MAPK), phospho-p38 MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2), and phospho-ERK1/2 was analyzed by western blotting. Activated macrophages were elicited through mineral oil lumbar injection, labeled with 1,19-dioctadecyl-3-3-39,39-tetramethylindocarbocyanine (DiI) and implanted into the corneal micro-pocket to induce CNV and to assess the antiangiogenic effect in rats. CNV was morphometrically analyzed using ImageJ software. Histopathological features were evaluated by immunofluorescence immunostaining for vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) on day 2 after surgery. In the present study, the results indicated that CNMs significantly inhibited the migration and invasion of HUVECs; remarkably attenuated the expression of VEGF, tumor necrosis factor-α, interleukin-1α, monocyte chemoattractant protein 1, cytokine-induced neutrophil chemoattractant 3, and MMP-9 protein; and downregulated ERK1/2, p38 MAPK, NF-κB activation, and HIF-1α expression in macrophages. The peritoneal cells elicited using mineral oil were highly purified macrophages, and the length and area of CNV were significantly decreased in the CNMs group compared with the control group. There was a significant reduction in the expression of VEGF and MMP-9 in activated macrophages and corneal tissue after pretreatment with CNMs in this model. In conclusion, CNMs potently suppressed macrophage-induced CNV via the inhibition of VEGF and MMP-9 expression. This effect might be mediated through attenuating macrophages via HIF-1α, MAPK, and NF-κB signaling pathways. Keywords: celastrol, nanomicelles, macrophages, corneal neovascularization
format	article
author	Li Z Li J Zhu L Zhang Y Zhang J Yao L Liang D Wang L
author_facet	Li Z Li J Zhu L Zhang Y Zhang J Yao L Liang D Wang L
author_sort	Li Z
title	Celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats
title_short	Celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats
title_full	Celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats
title_fullStr	Celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats
title_full_unstemmed	Celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats
title_sort	celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/764bf14f9c9c432ca5d8239cfd60a216
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Celastrol nanomicelles attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization in rats

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