A Transmembrane Mutation in FcgRIIb Reveals the Role of Ceramide in Phagocytosis and Autoimmunity

Abstract

Receptor-mediated phagocytosis is a phylogenetically ancient biological process employed for the protection of organisms from microbial infection and in the maintenance of tissue homeostasis. The best characterized cellular receptors that underlie this process are the FcgRs. The principal inhibitory receptor FcgRIIb is proposed to regulate phagocytosis, which is mediated by the activatory FcgRs. FcgRIIb also plays a role in controlling autoimmunity for a single Isoleucine to Threonine substitution in its transmembrane domain renders the receptor non-functional and confers susceptibility to systemic lupus erythematosus (SLE). Studies have found that this dysfunctional FcgRIIb receptor is excluded from membrane microdomains. In this study, we conduct a comprehensive analysis of the lipid composition of phagosomes as they invaginate, internalize and mature through the endocytic pathway from the macrophage plasma membrane. We also demonstrate that the dysfunctional FcgRIIb receptor impacts upon cellular ceramide expression and this is linked to the observed hyperaggressive phagocytic activity of these macrophages.