The phagocyte inhibitory receptor sirpα in the immune system

Phagocytes play a central role in the host defense against pathogens, by virtue of amongst other things their ability to recognize and destroy them. These processes have to be tightly controlled to prevent unwanted inflammation that could harm the host. From previous studies it has become clear that interactions between SIRPα expressed on phagocytes and CD47 on other cells are involved in the homeostatic control of immune effector functions, such as e.g. phagocytosis, against host cells. The research presented in this thesis aimed to explore whether SIRPα is also involved in the regulation of other previously unidentified aspects of phagocyte immunity. To do this we have investigated the role of SIRPα in regulating the phagocyte NADPH oxidase activity, its expression in various subtypes of acute myeloid leukemia and its role as a potential therapeutic target. We also explore the possibility of SIRP family members interacting with a CD47 homologue from the human poxvirus Variola, providing the basis for understanding the immunoregulatory role for vCD47 during poxviral infection. The last chapters of the thesis are dedicated to phagocyte migration and to explore the direct role of SIRPα signaling on neutrophils and macrophages motility during inflammatory processes.
The results described in this thesis support an important and versatile role of SIRPα in the regulation of phagocyte effector functions, while at the same time they do not raise major concerns for therapeutic targeting of the CD47-SIRPα pathway.