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Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion.
Li, Ting; Qian, Yixia; Li, Haicheng; Wang, Tongtong; Jiang, Qi; Wang, Yuchan; Zhu, Yanhua; Li, Shasha; He, Xuemin; Shi, Guojun; Su, Wenru; Lu, Yan; Chen, Yanming.
Afiliación
  • Li T; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • Qian Y; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • Li H; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • Wang T; Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • Jiang Q; Department of Ocular Immunology & Uveitis, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510515, China.
  • Wang Y; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • Zhu Y; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • Li S; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • He X; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • Shi G; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • Su W; Department of Ocular Immunology & Uveitis, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510515, China.
  • Lu Y; Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. luyan@gzhmu.edu.cn.
  • Chen Y; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. chyanm@mail.sysu.edu.cn.
Cell Commun Signal ; 22(1): 275, 2024 May 16.
Article en En | MEDLINE | ID: mdl-38755602
ABSTRACT

BACKGROUND:

Diabetic retinopathy (DR) is a major cause of blindness and is characterized by dysfunction of the retinal microvasculature. Neutrophil stasis, resulting in retinal inflammation and the occlusion of retinal microvessels, is a key mechanism driving DR. These plugging neutrophils subsequently release neutrophil extracellular traps (NETs), which further disrupts the retinal vasculature. Nevertheless, the primary catalyst for NETs extrusion in the retinal microenvironment under diabetic conditions remains unidentified. In recent studies, cellular communication network factor 1 (CCN1) has emerged as a central molecule modulating inflammation in pathological settings. Additionally, our previous research has shed light on the pathogenic role of CCN1 in maintaining endothelial integrity. However, the precise role of CCN1 in microvascular occlusion and its potential interaction with neutrophils in diabetic retinopathy have not yet been investigated.

METHODS:

We first examined the circulating level of CCN1 and NETs in our study cohort and analyzed related clinical parameters. To further evaluate the effects of CCN1 in vivo, we used recombinant CCN1 protein and CCN1 overexpression for gain-of-function, and CCN1 knockdown for loss-of-function by intravitreal injection in diabetic mice. The underlying mechanisms were further validated on human and mouse primary neutrophils and dHL60 cells.

RESULTS:

We detected increases in CCN1 and neutrophil elastase in the plasma of DR patients and the retinas of diabetic mice. CCN1 gain-of-function in the retina resulted in neutrophil stasis, NETs extrusion, capillary degeneration, and retinal leakage. Pre-treatment with DNase I to reduce NETs effectively eliminated CCN1-induced retinal leakage. Notably, both CCN1 knockdown and DNase I treatment rescued the retinal leakage in the context of diabetes. In vitro, CCN1 promoted adherence, migration, and NETs extrusion of neutrophils.

CONCLUSION:

In this study, we uncover that CCN1 contributed to retinal inflammation, vessel occlusion and leakage by recruiting neutrophils and triggering NETs extrusion under diabetic conditions. Notably, manipulating CCN1 was able to hold therapeutic promise for the treatment of diabetic retinopathy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Retinopatía Diabética / Proteína 61 Rica en Cisteína / Trampas Extracelulares / Neutrófilos Límite: Animals / Female / Humans / Male Idioma: En Revista: Cell Commun Signal Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Retinopatía Diabética / Proteína 61 Rica en Cisteína / Trampas Extracelulares / Neutrófilos Límite: Animals / Female / Humans / Male Idioma: En Revista: Cell Commun Signal Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido