Insulin inhibits inflammation-induced cone death in retinal detachment

J Neuroinflammation. 2020 Nov 26;17(1):358. doi: 10.1186/s12974-020-02039-1.


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 RD-associated cone death until the RD can be surgically repaired and improve visual outcome after RD.

Trial registration: NCT03318588.

Keywords: Cone degeneration; Inflammation; Insulin signaling; Mononuclear phagocytes; Retinal detachment.

MeSH terms

  • Adult
  • Animals
  • Cell Death / physiology
  • Eye Proteins / metabolism
  • Female
  • Glucose / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Insulin / pharmacology*
  • Male
  • Metformin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Retinal Cone Photoreceptor Cells / drug effects
  • Retinal Cone Photoreceptor Cells / metabolism*
  • Retinal Cone Photoreceptor Cells / pathology*
  • Retinal Detachment / immunology
  • Retinal Detachment / metabolism*
  • Retinal Detachment / pathology*
  • Rosiglitazone / pharmacology
  • Thioredoxins / metabolism


  • Eye Proteins
  • Hypoglycemic Agents
  • Insulin
  • RdCVF protein, mouse
  • Rosiglitazone
  • Thioredoxins
  • Metformin
  • Glucose

Associated data