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Experimental ImmunopathologyP.I.: Cecilia Garlanda, PhD
The main area of interest of the Laboratory of Experimental Immunopathology regards innate
immunity and in particular the regulation of inflammatory responses.
The receptor TIR8
The laboratory is engaged in the study of a soluble mediator of the innate immune response, the long pentraxin PTX3 (a molecule involved in the recognition of pathogens and inflammation) and a new long pentraxin, PTX4, identified by the group. The Laboratory also deals with a receptor member of the family of receptors IL-1R/TLR, TIR8 (which plays the role of negative control on inflammatory responses triggered by other members of the family). The methodological approach used consists in the analysis of the functional effect of genetic modifications of these molecules in different experimental models of infectious or inflammatory diseases. Main lines of research and results The pentraxin PTX3 PTX3 is a soluble receptor of innate immunity, identified by the group directed by Alberto Mantovani in the ‘90s. PTX3 belongs to the family of pentraxins, as C-reactive protein, a molecule widely used in the clinic as diagnostic marker of inflammation. PTX3 differs in some important features from C-reactive protein, such as the chemical structure and the cellular source, being composed of two functional domains and being produced by several different cell types. The Laboratory of Experimental Immunopathology contributed to define and characterize the biological activity of the long pentraxin PTX3 in the context of innate immune responses to pathogens of fungal, bacterial or viral origin, and in the regulation of inflammatory responses in the presence of pathogenic microorganisms or in condition of tissue damage, such as in acute myocardial infarction. The Laboratory identified the unique involvement of this molecule in female fertility and participated in studies aimed to evaluate its potential as diagnostic and prognostic marker in human diseases. A new line of research on this molecule concerns its involvement in tissue remodeling and tumor growth. The laboratory has recently identified a new long pentraxin, PTX4, for which is generating original reagents (antibodies, recombinant proteins, genetically modified animals) to study its function. TIR8 is a member of the family of receptors for interleukin-1, the prototypical inflammatory cytokine, and Toll Like Receptors (IL-1R/TLR), which are of extreme importance for the recognition of microorganisms and tissue damage. TIR8, identified by the group directed by Alberto Mantovani, differs from other family members, since it has the ability to negatively regulate the activation of cell signaling mediated by other family members (IL-1R, IL-18R, TLR4, TLR9 ... ). The cascade of events that is activated after the recognition of their ligands by these receptors leads to transcription of genes associated with inflammation and immunity, such as inflammatory cytokines, chemokines, reactive oxygen, and cell adhesion molecules essential for the defence. This cascade of events is finely controlled at different levels and by various regulatory mechanisms. The regulation of this inflammatory cascade is essential, as detrimental to the organism when excessively activated to or sustained, as occurs in pathological conditions such as sepsis or chronic inflammatory diseases. TIR8 represents a player of the negative control: it associates with molecules of the signaling pathway (such as IRAK) and reduces the activation of the transcription factor NFkB, which is essential for the synthesis of inflammatory molecules mentioned. The laboratory contributed to define the role of this molecule. The study of the phenotype of TIR8 gene targeted mice has allowed us to define the essential role of this molecule in various inflammatory conditions of infectious origin or based on tissue damage, such as in intestinal inflammation, in carcinogenesis associated with inflammation and in lung infections. Financial support The Laboratory of Experimental Immunopathology receives funding from the European Commission on the study of new molecules of innate immunity (HIIS), the Cystic Fibrosis Foundation for a project on opportunistic infections in cystic fibrosis, the Ministry of Health, Istituto Superiore di Sanità (Alliance Against Cancer), Foundation Cariplo, Italian Association for Cancer Research. |
Istituto Clinico Humanitas