Myelin regulates its own phagocytosis by simultaneous activation and down-regulation - a schematic representation of the working hypothesis and experimental design. (A & B) Degenerated wild-type CD47+/+ (CD47) myelin can simultaneously bind CR3 and SIRPα, which are expressed on microglia and macrophages. (A) Myelin binds CR3, which is the major receptor that mediates myelin phagocytosis in context of traumatic injury (see text), either directly or indirectly after being opsonized by complement protein C3bi (± C3bi). CR3 ligation initiates a signaling cascade that activates phagocytosis. (B) SIRPα ligation by myelin CD47 initiates a signaling cascade that inhibits phagocytosis by down-regulating signaling produced by CR3. (C & D) Augmentation of phagocytosis is anticipated if CD47 binding to SIRPα is blocked by either anti-SIRPα or anti-CD47 mAbs. (C) SIRPα on phagocytes is blocked by anti-SIRPα mAbs. (D) Myelin CD47 is blocked by anti-CD47 mAbs whose Fc-segments (black circle) are coated with anti-Fc-Fab2 fragments that lack their own Fc-segments. (E) Myelin CD47 is blocked by anti-CD47 mAbs whose Fc-segments are exposed. Consequently, CD47 binding to SIRPα is blocked (as in D) but binding to and activation of phagocytosis through FcγR is possible. (F) However, if anti-CD47 Fc-segments are coated by anti-Fc-Fab2 fragments (as in D), binding to and activation of phagocytosis through FcγR are blocked. Phagocytosis of (H) CD47+/+ is expected to be augmented after reduction of SIRPα levels in phagocytes; i.e. compared to phagocytosis of CD47+/+ by (G) phagocytes expressing normal SIRPα levels. Further, phagocytosis of CD47-/- myelin by phagocytes expressing (I) normal or (J) reduced SIRPα levels are expected to be about the same.