Inhibitor of apoptosis proteins (IAPs) expression in monocyte to macrophage differentiation and M1/M2 polarization

Abstract

Monocytes and macrophages constitute the first line of defense of the immune system against external pathogens and fulfill other essential roles in tissue homeostasis. The ability of monocytes to differentiate into macrophages constitutes an important asset in inflammatory situations because it allows for the quick recruitment of immune cells from the bloodstream to the site of infection. Furthermore, macrophages are highly plastic and can respond differently to changes in their environment and acquire a more cytotoxic and pro-inflammatory phenotype (M1) or a more healing and anti-inflammatory one (M2) and perform different roles during inflammation and resolution of inflammation. This polarization capacity enables the innate immune system to quickly respond to threatening situations faster than tissue specific differentiation or adaptive immune responses. Both processes, differentiation and polarization of macrophages, are important in inflammation resolution and their deregulation promotes the development of several pathologies, including cancer. On the other hand, macrophage activation syndrome (MAS), is a life-threatening complication of some rheumatic diseases, it is caused by an excessive activation and expansion of macrophages and T-lymphocytes. The inhibitor of apoptosis protein family (IAPs) has important roles in the regulation of several cellular processes and in innate and adaptive immune responses, specifically in many macrophage functions and almost every signaling pathway leading to NF-κB activation, which is implicated in pro-inflammatory cytokine production.

In this thesis we wanted to characterize the expression profile of IAPs in the differentiation of monocytes to macrophages and in polarization into M1/M2 states, study the effect of IAPs pharmacological inhibition in macrophage differentiation and polarization and analyze the possibility of IAPs targeting as a therapeutic approach for macro- phage activation syndrome.

En esta tesis queríamos evaluar la implicación de las proteínas inhibidoras de la apoptosis (IAPs, en inglés) en la diferenciación y polarización de macrófagos y estudiar la posibilidad de usar los IAPs como dianas terapéuticas en el tratamiento del síndrome de activación macrofágica.