Infectious diseases remain the second cause of human death worldwide and the first in developing countries. The emergence of antibiotic resistant strains has reinforced the importance of understanding host-pathogen dynamics and of identifying new avenues for therapeutic intervention. On the other hand, chronic inflammation represents one of the major causes of morbidity and mortality in western countries. Indeed, it is involved in the pathogenesis of several human diseases, such as cancer, atherosclerosis, allergy, inflammatory bowel diseases, autoimmune diseases and metabolic syndrome.
MITOCHONDRIAL ORCHESTRATION OF MACROPHAGE ACTIVATION
Macrophages have direct, crucial and complex roles in both infectious and inflammatory diseases but the cellular and molecular mechanisms responsible for tuning macrophage responses are still elusive, and this represents a major obstacle for the development of new treatments. In our laboratory, we are currently studying novel pathways controlling macrophage functions, with a particular focus on mitochondria. Mitochondria are intracellular organelles with several cellular functions, including energy conversion, regulation of metabolism, calcium signaling, and apoptosis. Mitochondria are highly mobile and accumulate in subcellular regions requiring high metabolic activity. We are studying the role of mitochondria in phagocytosis, macrophage polarization, and macrophage responses in vitro and in vivo.
Circulating leukocytes need to reach the inflamed tissues for an efficient immune response. To do this, they have to face several physical obstacles represented by the endothelial barrier and the intricate interstitial space; therefore, their ability to rapidly modify their shape is essential for immunity. The deformation of the nucleus, the largest and stiffest cellular organelle, represents the most challenging step during transendothelial migration.
In our lab, we are studying the signals that regulate the nuclear stiffness during cell migration in tissues. We believe that the identification of the molecular mechanisms affecting the biomechanical properties of the cell nuclei may pave the way to novel strategies to control inflammation as well as migration of cancer cells.
Neo-angiogenesis is a common feature of inflammatory conditions. The formation of new branches from a pre-existing vasculature is required to provide the sufficient amount of immune cells in the inflamed tissue. Thus, the control of this process may represent an effective strategy to suppress a pathological immune response. To do that, we are focusing on the employment of mesenchymal stem cells (MSCs), a heterogeneous population of adherent cells with self-renewable capacity and with a wide distribution in adult organism, to control angiogenesis. Indeed, we recently demonstrated that soluble factors secreted by MSCs exert immunosuppression, independently from the contact with other cell types, by interfering with the formation of new vessels. Although worldwide there are about 600 registered clinical trials evaluating the potential of MSCs-based cell therapy, this approach still remains far from a fully developed and safe clinical technology. To overcome all these issues, we are currently focusing on an alternative approach, exploiting products derived from MSCs, such as extracellular vesicles, rather than MSCs themselves, which may represent a cost-effective and safer approach.
- Bianca Calì
- Andrielly Agnellini
- Ricardo S. Rodriguez
- Sara Zumerle
- Roberta Angioni
- Elisabetta Marcuzzi
- Cristina Liboni
Selected PublicationsWang CM, Ploia C, Anselmi F, Sarukhan A, Viola A. . 2014. ATP acts as a paracrine signaling molecule to reduce the motility of T cells. EMBO J , 33(12):1354-64.
Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri PL, Monegal A, Rescigno M, Savino B, Colombo P, Jonjic N, Pecanic S, Lazzarato L, Fruttero R, Gasco A, Bronte V, Viola A. . 2011. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells.. The Journal of Experimental Medicine , 08(10):1949-62
R. Tavano, R.L. Contento, S.J. Baranda, M. Soligo, L. Tuosto, S. Manes and A. Viola. 2006. CD28 interaction with filamin-A controls lipid raft accumulation at the T cell immunological synapse. Nature Cell Biology, 8:1270-1276
S. Campello, R.A. Lacalle, M. Bettella, S. Manes, L. Scorrano and A. Viola. 2006. Orchestration of leukocyte chemotaxis by mitochondrial dynamycs. The Journal of Experimental Medicine, 203: 2879-2886
B. Molon, G. Gri, M. Bettella, C. Goumez-Mouton, A. Lanzavechia, C. Martinez-A, S. Manes and A. Viola. . 2005. T cell costimulation by chemokine receptors. Nature Immunology, 6:465-71
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