Lack of alphavbeta5 integrin receptor or its ligand MFG-E8: distinct effects on retinal function

Abstract

Background/aims: Diurnal phagocytosis of spent photoreceptor outer segment fragments by the retinal pigment epithelium (RPE) is critical for vision. We recently identified an important role for alphavbeta5 integrin receptors and their ligand Milk fat globule-EGF factor 8 (MFG-E8) in RPE phagocytosis.

Methods: We compared RPE phagocytosis and retinal function between mice deficient in alphavbeta5 integrin receptors and mice deficient in the secreted integrin ligand MFG-E8.

Results: Both beta5-/- and MFG-E8-/- mice exhibit the same phagocytic defect: RPE cells retain basal uptake activity but completely lack the burst of phagocytic activity as well as the rhythmic activation of Mer tyrosine kinase that follow circadian photoreceptor shedding in wild-type RPE. Strikingly, electroretinogram photoresponses decline with age only in beta5 -/- but not in MFG-E8-/- retina.

Conclusion: These results identify a critical role of alphavbeta5 integrin receptors and their ligand MFG-E8 in synchronizing retinal phagocytosis. Additionally, we show that lack of alphavbeta5 receptors and MFG-E8 ligand have distinct consequences for retinal function. These intriguing results suggest that loss of phagocytic rhythm is not solely responsible for the age-related blindness of beta5-/- mice.

Fig. 1

αvβ5- and MFG-E8-deficient RPE cells equally lack the daily rhythm of POS phagocytosis. a Both MFG-E8^−/− and β5^−/− RPE lack peak MerTK phosphorylation (PY-MerTK) 30 min after light onset, although MerTK protein levels are normal (MerTK). b Both MFG-E8^−/− and β5^−/− RPE lack peak phagosome residence found in wild-type RPE (^+/+) 2 h after light onset. Modified from Nandrot et al. [13], with permission from Rockefeller University Press, and from Nandrot et al. [14], with permission from the National Academy of Sciences.

Fig. 2

β5^−/− but not MFG-E8^−/− mice lose vision with age. Electroretinograms were recorded for wild-type and β5^−/− (a) as well as for MFG-E8^−/− and strain-matched control (b) mice between the ages of 4 months and 1 year. a At 1 year of age, scotopic electroretinogram responses of β5^−/− mice are significantly weaker than responses by wild-type mice. Both a- and b-wave amplitudes declined from 4 months of age in β5^−/− mice (black diamonds). Modified from Nandrot et al. [13], with permission from Rockefeller University Press. b Up to 1 year of age, scotopic electroretinogram responses of MFG-E8^−/− mice (dark grey triangles) do not significantly differ from responses of control mice (white circles). Student’s t test, n = 4–7, * p < 0.05, ** p < 0.01.