CD47 and signal regulatory protein a (SIRP a) modulates innate immune and autoimmune responses
The ability of the immune system to distinguish between self and non-self is key to avoid damage to host cells and tissues, where failure ultimately can lead to autoimmune disease. We have discovered a mechanism whereby macrophages (Mf) and dendritic cells (DC) can limit the risk of attacking host cells, by recognizing a cell surface protein which is ubiquitously expressed in the host. This protein is CD47 (Integrin-Associated Protein/IAP), which is recognized by the inhibitory receptor SIRPa (SHPS-1/BIT/P84) on Mf or DC. The interaction of these two proteins does not only regulate phagocytosis in Mf or DC in contact with another host cell, it is also found in neural tissues where it may be involved in regulating migration of nerve cells, formation of cell protrusions, and establishment of synapses. In bone, CD47 and SIRPa are involved in regulating the formation of bone-resorbing osteoclasts, cells which originate from hematopoietic precursors of the monocyte/macrophage lineage.
CD47 is a ubiquitously expressed cell surface glycoprotein, which can function as a ligand for the inhibitory myeloid receptor SIRPalpha. We have recently shown that CD47 can function as a marker of self on red blood cells (RBC) and lymphohematopoietic cells. CD47 activates the inhibitory receptor SIRPalpha on splenic macrophages or dendritic cells (DC), and the overriding negative signal generated prevents splenic macrophages or DC from phagocytosing self blood cells. This extends self vs. non-self discrimination to macrophages and DC (and likely also other SIRPalpha-expressing phagocytic cells like neutrophils). CD47-SIRPalpha interaction can also modulate Fcg and complement receptor-mediated phagocytosis, making CD47-deficient mice more sensitive to autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP).
Thus, our model propose, that to macrophages and DC all particles are "foreign" and targeted for elimination unless they carry the correct "passport": CD47. Our recent ongoing research suggest that CD47 or SIRPa expression can be regulated in various situations, such as apoptosis, infection and inflammation. In this way, the immune system may take advantage of the CD47/SIRPalpha-interaction to reduce the reactivity of SIRPalpha expressing cells to host cells and tissues. Thus, the contrast between CD47 expressing host cells, possible fiCD47-lowfl senescent cells and CD47-deficient microorganisms can be increased, resulting in reduced risk of damage to the host.