Chemokines in Immunity

Researchers: Valentina Cecchinato, Gianluca D’Agostino, Gabriela Danelon – Sargenti, Edisa Pirani, Ylenia Silvestri

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.

Projects

Chemokines: Structure/Function Studies

Group leaders: Mariagrazia Uguccioni
Researchers: Gianluca D’Agostino – PhD Student, Gabriela Danelon Sargenti -Technician
Status: In progress

Chemokines have emerged as key controllers of integrin function and cell locomotion. A vast range of in situ experiments has revealed that a variety of chemokines can be concomitantly produced in physiology, as well as in tumours. This renders the chemokine system a good target for therapy, and has increased the search, by pharmaceutical companies, for chemokine antagonists. While we understand well the effects of different chemokines one by one, much less was known about the potential consequences of the expression of multiple chemokines, cytokines, toll like receptor ligands or different inflammatory molecules, on cell responses to chemokines. Chemokine structure/function studies led us to identify chemokines that can act as natural antagonists by preventing natural agonist binding and the subsequent activation of the receptor. Recently, we have described chemokines that can act in synergism with chemokine receptor agonists, forming heterocomplexes able to induce functional responses at lower agonist concentration. There is no more doubt that the synergism between chemokines is crucial at the very early stage of inflammation, while the study of the role of molecules, such as the alarmin High Mobility Group Box 1 (HMGB1), that can synergise with chemokines is at its infancy.

Modulation of chemokine activity in the tissue microenvironment

Group leaders: Mariagrazia Uguccioni
Researchers: Gabriela Danelon Sargenti – Technician
Status: In progress

We have recently provided evidence that HMGB1, a damage associated molecular pattern protein (DAMP), can synergise with the CXCR4 agonist, CXCL12, promoting immune cell influx in injured tissues and enhancing immune cell responses. Cell income is blocked by glycyrrhizin, the sweet tasting compound of liquorice root, able to abolish the synergistic effect of HMGB1 on CXCL12-dependent migration, without affecting CXCL12/CXCR4 interaction. Given the fact that CXCL12 is strongly expressed in many tissues, favouring cell influx and egression, we aim to characterize in vitro and in vivo the mechanisms of action of chemokine synergy-inducing molecules on cell trafficking.

These studies might pave the way to establish novel approaches for controlling leukocyte migration and activities.

Responses to chemokines and trafficking at mucosal sites

Group leaders: Mariagrazia Uguccioni
Researchers: Valentina Cecchinato – Scientist, Gabriela Danelon Sargenti – Technician
Status: In progress

30 years after the discovery of human immunodeficiency virus (HIV) as the causative agent of AIDS, the mechanisms governing pathogenesis and disease progression are still not fully understood. Indeed, a progressive impairment of the immune system, with alterations that affect both innate and adaptive immunity, characterizes the infection with HIV‑1 in humans and with simian immunodeficiency virus (SIV) in macaques. It has been proposed that a state of chronic immune activation contributes to the loss of CD4⁺ T cells and to alterations of immune responses, ultimately leading to disease progression.

The loss of CD4⁺CCR5⁺ T cells in the gut associated lymphoid tissue (GALT) has been well documented both in the natural host and in pathogenic models of SIV infection. A decrease in the frequency of Th17 cells, a subset of effector T cells involved in the immune response against extracellular bacteria, has been described by Dr. Cecchinato in the mucosa of SIV infected animals. Nevertheless, the migratory capacity of this T cell subpopulation has not been investigated so far.

Chemokines are important mediators of leukocyte trafficking and function, and deregulation of their expression might contribute in part to the pathogenesis of HIV-1/SIV infection. In the frame of a projects funded by the European Community and by the Swiss HIV Cohort Study, we are investigating the mechanisms that mediate CCR6⁺/Th17 cells trafficking and activities at mucosal sites together with their decrease in frequency during HIV/SIV infection in order to better understand the pathogenesis of AIDS and in view of generating efficient vaccines.

Chemokines in Immunity

Institute for Research in Biomedicine

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