Insulin inhibits inflammation-induced cone death in retinal detachment
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...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-11-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-020-02039-1 |
| _version_ | 1819298507772657664 |
|---|---|
| author | Jean-Baptiste Conart Guillaume Blot Sébastien Augustin Géraldine Millet-Puel Christophe Roubeix Fanny Beguier Hugo Charles-Messance Sara Touhami José-Alain Sahel Jean-Paul Berrod Thierry Léveillard Xavier Guillonneau Cécile Delarasse Florian Sennlaub |
| author_facet | Jean-Baptiste Conart Guillaume Blot Sébastien Augustin Géraldine Millet-Puel Christophe Roubeix Fanny Beguier Hugo Charles-Messance Sara Touhami José-Alain Sahel Jean-Paul Berrod Thierry Léveillard Xavier Guillonneau Cécile Delarasse Florian Sennlaub |
| author_sort | Jean-Baptiste Conart |
| collection | DOAJ |
| description | 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 RD-associated cone death until the RD can be surgically repaired and improve visual outcome after RD. Trial registration ClinicalTrials.gov NCT03318588 |
| first_indexed | 2024-12-24T05:31:00Z |
| format | Article |
| id | doaj.art-d3b70a8884584bef8296201e33f43b57 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-24T05:31:00Z |
| publishDate | 2020-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-d3b70a8884584bef8296201e33f43b572022-12-21T17:13:11ZengBMCJournal of Neuroinflammation1742-20942020-11-0117111510.1186/s12974-020-02039-1Insulin inhibits inflammation-induced cone death in retinal detachmentJean-Baptiste Conart0Guillaume Blot1Sébastien Augustin2Géraldine Millet-Puel3Christophe Roubeix4Fanny Beguier5Hugo Charles-Messance6Sara Touhami7José-Alain Sahel8Jean-Paul Berrod9Thierry Léveillard10Xavier Guillonneau11Cécile Delarasse12Florian Sennlaub13Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéDépartement d’Ophtalmologie, CHRU NancyInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéInstitut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne UniversitéAbstract 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 ClinicalTrials.gov NCT03318588https://doi.org/10.1186/s12974-020-02039-1Retinal detachmentCone degenerationInflammationMononuclear phagocytesInsulin signaling |
| spellingShingle | Jean-Baptiste Conart Guillaume Blot Sébastien Augustin Géraldine Millet-Puel Christophe Roubeix Fanny Beguier Hugo Charles-Messance Sara Touhami José-Alain Sahel Jean-Paul Berrod Thierry Léveillard Xavier Guillonneau Cécile Delarasse Florian Sennlaub Insulin inhibits inflammation-induced cone death in retinal detachment Journal of Neuroinflammation Retinal detachment Cone degeneration Inflammation Mononuclear phagocytes Insulin signaling |
| title | Insulin inhibits inflammation-induced cone death in retinal detachment |
| title_full | Insulin inhibits inflammation-induced cone death in retinal detachment |
| title_fullStr | Insulin inhibits inflammation-induced cone death in retinal detachment |
| title_full_unstemmed | Insulin inhibits inflammation-induced cone death in retinal detachment |
| title_short | Insulin inhibits inflammation-induced cone death in retinal detachment |
| title_sort | insulin inhibits inflammation induced cone death in retinal detachment |
| topic | Retinal detachment Cone degeneration Inflammation Mononuclear phagocytes Insulin signaling |
| url | https://doi.org/10.1186/s12974-020-02039-1 |
| work_keys_str_mv | AT jeanbaptisteconart insulininhibitsinflammationinducedconedeathinretinaldetachment AT guillaumeblot insulininhibitsinflammationinducedconedeathinretinaldetachment AT sebastienaugustin insulininhibitsinflammationinducedconedeathinretinaldetachment AT geraldinemilletpuel insulininhibitsinflammationinducedconedeathinretinaldetachment AT christopheroubeix insulininhibitsinflammationinducedconedeathinretinaldetachment AT fannybeguier insulininhibitsinflammationinducedconedeathinretinaldetachment AT hugocharlesmessance insulininhibitsinflammationinducedconedeathinretinaldetachment AT saratouhami insulininhibitsinflammationinducedconedeathinretinaldetachment AT josealainsahel insulininhibitsinflammationinducedconedeathinretinaldetachment AT jeanpaulberrod insulininhibitsinflammationinducedconedeathinretinaldetachment AT thierryleveillard insulininhibitsinflammationinducedconedeathinretinaldetachment AT xavierguillonneau insulininhibitsinflammationinducedconedeathinretinaldetachment AT ceciledelarasse insulininhibitsinflammationinducedconedeathinretinaldetachment AT floriansennlaub insulininhibitsinflammationinducedconedeathinretinaldetachment |