Regualtion of inflammation by CD222

The ability of immune cells to migrate into tissue is crucial for the inflammatory process, the major defense mechanism of the human body`s immune system against pathogens. However, deregulated cell motility is a major characteristic of serious inflammatory disorders found in autoimmunity and allergy. Migration is a multistep process including pericellular proteolysis, cell adhesion, signal transduction and chemotaxis. Although there is considerable knowledge how these processes are initiated and activated, little is known which molecules are involved in controlling and executing their downregulation and dampening. Therefore, we are aiming in this project to uncover molecules and signaling pathways with negative regulatory function in migration with the final goal to define targets to pharmacologically control this mechanism when aberrantly activated. We will focus on the mannose 6-phosphate/insulin-like growth factor 2 receptor, also termed CD222, because our up-to-now data strongly indicate its negative regulatory function in cell migration. In particular, we will study in detail the molecular mechanisms how CD222 exerts its negative regulatory function. Basically we will 1) perform loss-of- function and gain-of-function experiments using siRNA and transfection technology as well as novel biochemical and imaging methods, and 2) prove CD222 as target to modulate migration of immune cells; we already have identified peptides derived from CD222 that can block cell migration. The obtained knowledge should allow the design of novel strategies and tools for therapeutic interventions in pathologies accompanied with deregulated migratory processes such as chronic, allergic or autoimmune inflammatory diseases.

The project entitled "Regulatory functions of the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R, CD222) in inflammatory processes" (P19014), aimed to characterize the specific role of M6P/IGF2R in cell migration, latent transforming growth beta activation and angiogenesis. In the frame of the project, we have uncovered mechanisms how M6P/IGF2R exerts its tumour suppressive activities. In particular, we have discovered that M6P/IGF2R controls cell invasion by regulating alpha-V integrin expression and by accelerating urokinase- type plasminogen activator receptor (uPAR) cleavage leading to the loss of uPA/vitronectin/integrin-binding sites on migratory cells. In addition, we have found that the tumour necrosis factor convertase (TACE, ADAM-17) mediates the release of M6P/IGF2R`s ectodomain, which in turn prevents Plg from binding to the cell surface, ultimately inhibiting in this manner Plg activation. Furthermore, we have identified a peptide derived from the Plg- binding site of M6P/IGF2R, which mimics sM6P/IGF2R in the inhibition of Plg activation, and blocks angiogenesis and cancer cell invasion. Finally, we identified several novel ligands of M6P/IGF2R, all crucially involved in regulation of immune responses. All together, our work contributed significantly to the knowledge of regulatory mechanisms associated to M6P/IGF2R.