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The main area of interest of the Laboratory regards the innate immunity and the regulation of
inflammatory responses.
The laboratory contributed to define and characterize 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 characterized
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 or skin wound healing. The Laboratory also identified and characterized
TIR8/SIGIRR, a member of the family of Interleukin-1Receptors/Toll Like Receptors. TIR8 is a
negative regulator of inflammatory responses triggered by other members of the family and is
involved in different pathological conditions, ranging from infections and inflammation to
autoimmunity and cancer.
The methodological approaches used by the Laboratory consist in the analysis of the
functional effect of genetic modifications of these molecules in different experimental animal
models of infectious or inflammatory diseases and in cancer and to translate these information to
human 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 hepatic
acute phase 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. An effort shared with other groups of the Institute is focused
on the transfer of this molecule to the clinic, as potential diagnostic biomarker and in therapy of
opportunistic infections in immunocompromised patient.
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.
The receptor TIR8/SIGIRR
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 (such as IL-1R, IL-18R, ST2, 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, since it is detrimental to
the organism when excessively activated or sustained, for instance 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
above. 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 lung infections and in carcinogenesis associated with inflammation. |
Istituto Clinico Humanitas