Chemokines in Immunity
Mariagrazia Uguccioni, Group Leader
Our research interest remains focused on cell trafficking in human physiology and pathology, with an emphasis on the mechanisms governing fine-tuning modulation of chemokine expression and activity, in order to identify novel therapeutic target for pharmacological intervention. Chemokines are secreted proteins, emerged as key controllers of integrin function and cell locomotion. The effects of chemokines are mediated by seven transmembrane domain receptors coupled to GTP-binding proteins, which are differentially expressed in a wide range of cell types. The resulting combinatorial diversity in responsiveness to chemokines guarantees the proper tissue distribution of distinct leukocyte subsets under normal and inflammatory/pathological conditions. Directional guidance of cells via gradients of chemokines is considered crucial, but we often lack in many pathological conditions, a direct evidence of chemokine receptor functionality, which may be relevant in the development of the disease, and can be modulated by the therapy. During the inflammatory response, from the onset to the chronic phase and even in the case of autoimmune diseases, the sequential release of exogenous agents (e.g.: bacterial and viral products) and induction of endogenous mediators (e.g.: cytokines, chemokines and alarmins) contributes to the recruitment of circulating leukocytes to the inflamed site. There are many different ways to enhance or reduce the inflammatory response and to fine tune leukocytes recruitment. We have described a novel regulatory mechanism of leukocyte migration that shows how several non-ligand chemokines may trigger leukocytes to respond to agonist concentrations that per se would be inactive, thus lowering their “migratory threshold” ability. However, very little is known about the capacity of non-ligand molecules, other than chemokines, to synergize with chemokine agonists. Our studies are now focusing on chronic inflammatory diseases, such as Rheumatoid Arthritis and Ankylosing Spondylitis, and on the role, chemokine heterocomplexes may have on the development of the disease. In parallel to the study of chemokine activities, we are now focusing on the modulation of the activity of chemokine receptors, that might occurs in chronic inflammation. These studies might shed new light on novel pharmacological interventions aimed at dampening and resolving inflammation.