Insulin inhibits inflammation-induced cone death in retinal detachment
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(2020) 17:358
RESEARCH
Open Access
Insulin inhibits inflammation-induced cone death in retinal detachment Jean-Baptiste Conart1,2 , Guillaume Blot1, Sébastien Augustin1, Géraldine Millet-Puel1, Christophe Roubeix1, Fanny Beguier1, Hugo Charles-Messance1, Sara Touhami1, José-Alain Sahel1, Jean-Paul Berrod2, Thierry Léveillard1, Xavier Guillonneau1*, Cécile Delarasse1* and Florian Sennlaub1*
Abstract Background: Rhegmatogenous retinal detachment (RD) involving the macula is a major cause of visual impairment despite high surgical success rate, mainly because of cone death. RD causes the infiltration of activated immune cells, but it is not clear whether and how infiltrating inflammatory cells contribute to cone cell loss. Methods: Vitreous samples from patients with RD and from control patients with macular hole were analyzed to characterize the inflammatory response to RD. A mouse model of RD and retinal explants culture were then used to explore the mechanisms leading to cone death. Results: Analysis of vitreous samples confirms that RD induces a marked inflammatory response with increased cytokine and chemokine expression in humans, which is closely mimicked by experimental murine RD. In this model, we corroborate that myeloid cells and T-lymphocytes contribute to cone loss, as the inhibition of their accumulation by Thrombospondin 1 (TSP1) increased cone survival. Using monocyte/retinal co-cultures and TSP1 treatment in RD, we demonstrate that immune cell infiltration downregulates rod-derived cone viability factor (RdCVF), which physiologically regulates glucose uptake in cones. Insulin and the insulin sensitizers rosiglitazone and metformin prevent in part the RD-induced cone loss in vivo, despite the persistence of inflammation Conclusion: Our results describe a new mechanism by which inflammation induces cone death in RD, likely through cone starvation due to the downregulation of RdCVF that could be reversed by insulin. Therapeutic inhibition of inflammation and stimulation of glucose availability in cones by insulin signaling might prevent RDassociated cone death until the RD can be surgically repaired and improve visual outcome after RD. Trial registration: ClinicalTrials.gov NCT03318588 Keywords: Retinal detachment, Cone degeneration, Inflammation, Mononuclear phagocytes, Insulin signaling
Background Rhegmatogenous retinal detachment (RD) is a sightthreatening condition with an annual incidence of 10.5 per 100,000 people [1]. Advances in surgical techniques over recent decades have greatly improved the anatomical results * Correspondence: [email protected]; [email protected]; [email protected] 1 Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012 Paris, France Full list of author information is available at the end of the article
with a primary success rate currently up to 80% [2]. However, despite a successful retinal reattachment, visual recovery may still be disappointing, especially in cases involving the cone-rich macula [3] a
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