Modulation of diabetes-related retinal pathophysiology by PTX3.

Autor:	Pathak V; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Bertelli PM; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Pedrini E; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Harkin K; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Peixoto E; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Allen LD; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Mcloughlin K; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Chavda ND; Department for Eye and Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, United Kingdom., Hamill KJ; Department for Eye and Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, United Kingdom., Guduric-Fuchs J; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Inforzato A; Laboratory of Cellular and Humoral Innate Immunity, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Milan 20089, Italy.; Department of Biomedical Sciences, Humanitas University, Milan 20072, Italy., Bottazzi B; Laboratory of Cellular and Humoral Innate Immunity, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Milan 20089, Italy., Stitt AW; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom., Medina RJ; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, United Kingdom.; Department for Eye and Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, United Kingdom.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 08; Vol. 121 (41), pp. e2320034121. Date of Electronic Publication: 2024 Sep 30.
DOI:	10.1073/pnas.2320034121
Abstrakt:	Diabetic retinopathy (DR) is a common complication of diabetes characterized by vascular pathology and neuroinflammation. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule that functions at the crossroads between innate immunity, inflammation, and tissue remodeling. DR is known to involve inflammatory pathways, although the potential relevance of PTX3 has not been explored. We found that PTX3 protein levels increased in the retina of diabetic mice. Similarly, evaluation of a publicly available transcriptomic human dataset revealed increased PTX3 expression in DR with diabetic macular edema and proliferative retinopathy, when compared to nondiabetic retinas or diabetic retinas without complications. To further understand the role of PTX3 within DR, we employed the streptozotocin-induced diabetes model in PTX3 knockout mice (PTX3 KO ), which were followed up for 9 mo to evaluate hallmarks of disease progression. In diabetic PTX3 KO mice, we observed decreased reactive gliosis, diminished microglia activation, and reduced vasodegeneration, when compared to diabetic PTX3 wild-type littermates. The decrease in DR-associated pathological features in PTX3 KO retinas translated into preserved visual function, as evidenced by improved optokinetic response, restored b-wave amplitude in electroretinograms, and attenuated neurodegeneration. We showed that PTX3 induced an inflammatory phenotype in human retinal macroglia, characterized by GFAP upregulation and increased secretion of IL6 and PAI-1. We confirmed that PTX3 was required for TNF-α-induced reactive gliosis, as PTX3 KO retinal explants did not up-regulate GFAP in response to TNF-α. This study reveals a unique role for PTX3 as an enhancer of sterile inflammation in DR, which drives pathogenesis and ultimately visual impairment. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu