The Immune Response is a Critical Regulator of Zebrafish Retinal Pigment Epithelium Regeneration

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 May 19

PMID 34006636

Citations 24

Authors

Lyndsay L Leach

Nicholas J Hanovice

Stephanie M George

Ana E Gabriel

Jeffrey M Gross

Affiliations

Soon will be listed here.

Abstract

Loss of the retinal pigment epithelium (RPE) because of dysfunction or disease can lead to blindness in humans. Harnessing the intrinsic ability of the RPE to self-repair is an attractive therapeutic strategy; however, mammalian RPE is limited in its regenerative capacity. Zebrafish possess tremendous intrinsic regenerative potential in ocular tissues, including the RPE, but little is known about the mechanisms driving RPE regeneration. Here, utilizing transgenic and mutant zebrafish lines, pharmacological manipulations, transcriptomics, and imaging analyses, we identified elements of the immune response as critical mediators of intrinsic RPE regeneration. After genetic ablation, the RPE express immune-related genes, including leukocyte recruitment factors such as We demonstrate that macrophage/microglia cells are responsive to RPE damage and that their function is required for the timely progression of the regenerative response. These data identify the molecular and cellular underpinnings of RPE regeneration and hold significant potential for translational approaches aimed toward promoting a pro-regenerative environment in mammalian RPE.

Citing Articles

Interleukin-34 and debris clearance by mononuclear phagocytes drive retinal pigment epithelium regeneration in zebrafish.

Leach L, Gonzalez R, Jayawardena S, Gross J bioRxiv. 2025; .

PMID: 39868193 PMC: 11761032. DOI: 10.1101/2025.01.10.632236.

Apoptotic extracellular vesicles carrying Mif regulate macrophage recruitment and compensatory proliferation in neighboring epithelial stem cells during tissue maintenance.

Essien S, Ahuja I, Eisenhoffer G PLoS Biol. 2024; 22(11):e3002194.

PMID: 39495793 PMC: 11578469. DOI: 10.1371/journal.pbio.3002194.

Damage-Induced Senescent Immune Cells Regulate Regeneration of the Zebrafish Retina.

Konar G, Flickinger Z, Sharma S, Vallone K, Lyon Jr C, Doshier C Aging Biol. 2024; 2.

PMID: 39156966 PMC: 11328971. DOI: 10.59368/agingbio.20240021.

Minimal-Invasive 3D Laser Printing of Microimplants in Organismo.

Afting C, Mainik P, Vazquez-Martel C, Abele T, Kaul V, Kale G Adv Sci (Weinh). 2024; 11(30):e2401110.

PMID: 38864352 PMC: 11321634. DOI: 10.1002/advs.202401110.

Macrophages modulate fibrosis during newt lens regeneration.

Tsissios G, Sallese A, Perez-Estrada J, Tangeman J, Chen W, Smucker B Stem Cell Res Ther. 2024; 15(1):141.

PMID: 38745238 PMC: 11094960. DOI: 10.1186/s13287-024-03740-1.

References

Salero E, Blenkinsop T, Corneo B, Harris A, Rabin D, Stern J . Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives. Cell Stem Cell. 2012; 10(1):88-95. DOI: 10.1016/j.stem.2011.11.018. View

Ehrchen J, Roth J, Barczyk-Kahlert K . More Than Suppression: Glucocorticoid Action on Monocytes and Macrophages. Front Immunol. 2019; 10:2028. PMC: 6718555. DOI: 10.3389/fimmu.2019.02028. View

Kyritsis N, Kizil C, Zocher S, Kroehne V, Kaslin J, Freudenreich D . Acute inflammation initiates the regenerative response in the adult zebrafish brain. Science. 2012; 338(6112):1353-6. DOI: 10.1126/science.1228773. View

Reinhardt R, Centanin L, Tavhelidse T, Inoue D, Wittbrodt B, Concordet J . Sox2, Tlx, Gli3, and Her9 converge on Rx2 to define retinal stem cells in vivo. EMBO J. 2015; 34(11):1572-88. PMC: 4474531. DOI: 10.15252/embj.201490706. View

Walker F, Beynon S, Jones K, Zhao Z, Kongsui R, Cairns M . Dynamic structural remodelling of microglia in health and disease: a review of the models, the signals and the mechanisms. Brain Behav Immun. 2014; 37:1-14. DOI: 10.1016/j.bbi.2013.12.010. View

Chiba C . The retinal pigment epithelium: an important player of retinal disorders and regeneration. Exp Eye Res. 2013; 123:107-14. DOI: 10.1016/j.exer.2013.07.009. View

Shi D, Yang D, Yan B . Dexamethasone transcriptionally increases the expression of the pregnane X receptor and synergistically enhances pyrethroid esfenvalerate in the induction of cytochrome P450 3A23. Biochem Pharmacol. 2010; 80(8):1274-83. PMC: 2933965. DOI: 10.1016/j.bcp.2010.06.043. View

Ma W, Zhang Y, Gao C, Fariss R, Tam J, Wong W . Monocyte infiltration and proliferation reestablish myeloid cell homeostasis in the mouse retina following retinal pigment epithelial cell injury. Sci Rep. 2017; 7(1):8433. PMC: 5559448. DOI: 10.1038/s41598-017-08702-7. View

Loynes C, Lee J, Robertson A, Steel M, Ellett F, Feng Y . PGE production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo. Sci Adv. 2018; 4(9):eaar8320. PMC: 6124908. DOI: 10.1126/sciadv.aar8320. View

10.

Zhang C, Lam T, Tso M . Heterogeneous populations of microglia/macrophages in the retina and their activation after retinal ischemia and reperfusion injury. Exp Eye Res. 2005; 81(6):700-9. DOI: 10.1016/j.exer.2005.04.008. View

11.

Sandoval A, Maden M . Regeneration in the spiny mouse, Acomys, a new mammalian model. Curr Opin Genet Dev. 2020; 64:31-36. PMC: 9724456. DOI: 10.1016/j.gde.2020.05.019. View

12.

Harvie E, Green J, Neely M, Huttenlocher A . Innate immune response to Streptococcus iniae infection in zebrafish larvae. Infect Immun. 2012; 81(1):110-21. PMC: 3536132. DOI: 10.1128/IAI.00642-12. View

13.

Chatzopoulou A, Heijmans J, Burgerhout E, Oskam N, Spaink H, Meijer A . Glucocorticoid-Induced Attenuation of the Inflammatory Response in Zebrafish. Endocrinology. 2016; 157(7):2772-84. DOI: 10.1210/en.2015-2050. View

14.

Mescher A . Macrophages and fibroblasts during inflammation and tissue repair in models of organ regeneration. Regeneration (Oxf). 2017; 4(2):39-53. PMC: 5469729. DOI: 10.1002/reg2.77. View

15.

Ghazi N, Abboud E, Nowilaty S, Alkuraya H, Alhommadi A, Cai H . Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial. Hum Genet. 2016; 135(3):327-43. DOI: 10.1007/s00439-016-1637-y. View

16.

Li L, Yan B, Shi Y, Zhang W, Wen Z . Live imaging reveals differing roles of macrophages and neutrophils during zebrafish tail fin regeneration. J Biol Chem. 2012; 287(30):25353-60. PMC: 3408142. DOI: 10.1074/jbc.M112.349126. View

17.

Lam P, Yoo S, Green J, Huttenlocher A . The SH2-domain-containing inositol 5-phosphatase (SHIP) limits the motility of neutrophils and their recruitment to wounds in zebrafish. J Cell Sci. 2012; 125(Pt 21):4973-8. PMC: 3533387. DOI: 10.1242/jcs.106625. View

18.

Petrie T, Strand N, Yang C, Tsung-Yang C, Rabinowitz J, Moon R . Macrophages modulate adult zebrafish tail fin regeneration. Development. 2014; 141(13):2581-91. PMC: 4067955. DOI: 10.1242/dev.098459. View

19.

Mehat M, Sundaram V, Ripamonti C, Robson A, Smith A, Borooah S . Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. Ophthalmology. 2018; 125(11):1765-1775. PMC: 6195794. DOI: 10.1016/j.ophtha.2018.04.037. View

20.

White D, Sengupta S, Saxena M, Xu Q, Hanes J, Ding D . Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina. Proc Natl Acad Sci U S A. 2017; 114(18):E3719-E3728. PMC: 5422825. DOI: 10.1073/pnas.1617721114. View