Advertisement

αvβ5 Integrin-Dependent Diurnal Phagocytosis of Shed Photoreceptor Outer Segments by RPE Cells Is Independent of the Integrin Coreceptor Transglutaminase-2

  • Linda Ruggiero
  • Zsolt Sarang
  • Zsuzsa Szondy
  • Silvia C. FinnemannEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

Diurnal phagocytosis of shed photoreceptor outer segments (POS) by the underlying retinal pigment epithelium (RPE) is essential for vision. RPE receptor proteins identified thus far to play a role in recognition and engulfment of POS include the integrin receptor αvβ5, the tyrosine kinase MerTK, and the scavenger receptor CD36. These receptors have in common that they also contribute to phagocytosis of apoptotic cells by other phagocytic cell types. Tissue transglutaminase 2 (TG2) is a multifunctional enzyme with several functions in the cytoplasm and as a component of the extracellular matrix. Complex formation of extracellular TG2 with αvβ3 integrin receptors facilitates phagocytosis of apoptotic cells by macrophages. Here, we investigated whether TG2 also plays a role in diurnal POS phagocytosis by RPE cells that depends on αvβ5 integrin, which is closely related to αvβ3. To this end, we examined retinal morphology and RPE phagocytic activity in TG2 knockout (TG2−/−) mice. TG2−/− retinas showed no obvious abnormalities in mice of 2 or 12 months of age. Furthermore, quantification of numbers of POS phagosomes in the RPE in situ at different times of day revealed a robust peak of phagosomes in TG2 null RPE at 1 h after light onset but minimal phagosomes 8 h later. Thus, RPE cells lacking TG2 phagocytose POS in a diurnal rhythm like wild-type RPE cells and unlike RPE cells lacking αvβ5 integrin. These data indicate that TG2 is not required for RPE-mediated phagocytosis of shed POS.

Keywords

Photoreceptor outer segment renewal Retinal pigment epithelium Phagocytosis Integrins Transglutaminase 2 Knockout mice Retina 

Notes

Acknowledgments

These studies were supported by NIH grant EY-13295 to S.C.F. and Hungarian Research Fund OTKA 77587 to Z.S.

References

  1. Akimov SS, Krylov D, Fleischman LF et al (2000) Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. J Cell Biol 148:825–838PubMedCrossRefGoogle Scholar
  2. Akimov SS, Belkin AM (2001) Cell-surface transglutaminase promotes fibronectin assembly via interaction with the gelatin-binding domain of fibronectin: a role in TGFβ-dependent matrix deposition. J Cell Sci 114:2989–3000PubMedGoogle Scholar
  3. Albert M, Pearce SFA, Francisco LM et al (1998) Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 188:1359–1368PubMedCrossRefGoogle Scholar
  4. Chang Y, Finnemann SC (2007) Tetraspanin CD81 is required for the αvβ5 integrin-dependent particle-binding step of RPE phagocytosis. J Cell Sci 120:3053–3063PubMedCrossRefGoogle Scholar
  5. De Laurenzi V, Melino G (2001) Gene disruption of tissue transglutaminase. Mol Cell Biol 21: 148–155PubMedCrossRefGoogle Scholar
  6. Finnemann SC, Rodriguez-Boulan E (1999) Macrophage and retinal pigment epithelium phagocytosis: apoptotic cells and photoreceptors compete for αvβ3 and αvβ5 integrins, and protein kinase C regulates αvβ5 binding and cytoskeletal linkage. J Exp Med 190:861–874PubMedCrossRefGoogle Scholar
  7. Finnemann SC, Bonilha VL, Marmorstein AD et al (1997) Phagocytosis of rod outer segments by retinal pigment epithelial cells requires αvβ5 integrin for binding but not for internalization. Proc Natl Acad Sci USA 94:12932–12937PubMedCrossRefGoogle Scholar
  8. Hodrea J, Demeny MA, Majai G et al (2010) Transglutaminase 2 is expressed and active on the surface of human monocyte-derived dendritic cells and macrophages. Immunol Lett 130:74–81PubMedCrossRefGoogle Scholar
  9. LaVail MM (1976) Rod outer segment disk shedding in rat retina: relationship to cyclic lighting. Science 194:1071–1074PubMedCrossRefGoogle Scholar
  10. Lucas M, Stuart LM, Zhang A et al (2006) Requirements for apoptotic cell contact in regulation of macrophage responses. J Immunol 177:4047–4054PubMedGoogle Scholar
  11. Nandrot EF, Kim Y, Brodie SE et al (2004) Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking αvβ5 integrin. J Exp Med 200:1539–1545PubMedCrossRefGoogle Scholar
  12. Nandrot EF, Anand M, Almeida D et al (2007) Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis. Proc Natl Acad Sci USA 104:12005–12010PubMedCrossRefGoogle Scholar
  13. Savill J, Dransfield I, Gregory C et al (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965–975PubMedCrossRefGoogle Scholar
  14. Szondy Z, Sarang Z, Molnar P et al (2003) Transglutaminase 2−/− mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells. Proc Natl Acad Sci USA 100:7812–7817PubMedCrossRefGoogle Scholar
  15. Toth B, Garabuczi E, Sarang Z et al (2009a) Transglutaminase 2 is needed for the formation of an efficient phagocyte portal in macrophages engulfing apoptotic cells. J Immunol 182:2084–2092PubMedCrossRefGoogle Scholar
  16. Toth B, Sarang Z, Vereb G et al (2009b) Over-expression of integrin β3 can partially overcome the defect of integrin β3 signaling in transglutaminase 2 null macrophages. Immunol Lett 126:22–28PubMedCrossRefGoogle Scholar
  17. Zemskov EA, Janiak A, Hang J et al (2006) The role of tissue transglutaminase in cell-matrix interactions. Front Biosci 11:1057–1076PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Linda Ruggiero
    • 1
  • Zsolt Sarang
    • 2
  • Zsuzsa Szondy
    • 2
  • Silvia C. Finnemann
    • 1
    Email author
  1. 1.Department of Biological SciencesFordham UniversityBronxUSA
  2. 2.Department of Biochemistry and Molecular Biology, Apoptosis and Genomics Research Group, Hungarian Academy of SciencesUniversity of DebrecenDebrecenHungary

Personalised recommendations