Macrophage and retinal pigment epithelium phagocytosis: apoptotic cells and photoreceptors compete for alphavbeta3 and alphavbeta5 integrins, and protein kinase C regulates alphavbeta5 binding and cytoskeletal linkage.
Noninflammatory monocyte macrophages use alphavbeta3 integrin to selectively bind apoptotic cells, initiating their phagocytic removal. In a related process, the retinal pigment epithelium (RPE) employs alphavbeta5 integrin to recognize spent photoreceptor outer segment particles (OS). Here, we show that apoptotic cells and OS compete for binding to these receptors, indicating that OS and apoptotic cells expose surface signals recognizable by alphavbeta3 and alphavbeta5. Particle binding to alphavbeta5 required protein kinase C (PKC) activation. In RPE, alphavbeta5 binding was maximally activated even before any phagocytic challenge and was reduced by PKC inhibitors. In macrophages, it was dormant but became activated upon PKC stimulation. PKC-activated alphavbeta5-mediated binding in macrophages differed from constitutive binding to the same integrin receptor in RPE cells in that the former followed much faster kinetics, similar to particle binding mediated by alphavbeta3. Activation of alphavbeta5 for particle binding correlated with its recruitment into a detergent-insoluble fraction, a process sensitive to pharmacological modulation of PKC in both types of phagocytes. Furthermore, alphavbeta5 but not alphavbeta3 particle binding required actin microfilaments. These data constitute the first evidence that noninflammatory phagocytes actively regulate the earliest phase of phagocytic clearance, particle binding, by controlling receptor activity.
Finnemann
S C
SC
Department of Ophthalmology, Margaret M. Dyson Vision Institute, New York, New York 10021, USA. sfinne@mail.med.cornell.edu
Rodriguez-Boulan
E
E
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D016023:Integrins / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010587:Phagocytosis; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D019030:Receptors, Vitronectin / Q000502:physiology*; D015398:Signal Transduction
D016023:Integrins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D011493:Protein Kinase C