Cytokine regulatory pathways in aging and aging associated pathologies
Innate immunity is a common denominator of diverse pathologies including those associated with aging, such as atherosclerosis. The action of innate immunity receptors and inflammatory cytokines is under strict control by negative regulators. These include anti inflammatory/immunosuppressive cytokines such as the IL-1 receptor antagonist, decoy receptors and inhibitory receptors. This group has contributed to the identification and definition of molecules and pathways involved in negative regulation of innate immunity receptors and cytokines, as well as of fluid phase pattern recognition receptors. These include isoforms of the IL-1 receptor antagonist, the type II IL-1 receptor as a decoy, the D6 chemokine receptor as a decoy for inflammatory CC chemokines, the inhibitory orphan receptor TIR8/SIGIRR and the long pentraxin PTX3. The group has developed original tool for these molecules including antibodies, immuno assays, gene modified mice. These will be part of the common shared platform of the project. A special focus of our effort will be on the long pentraxin PTX3. PTX3 is a fluid phase pattern recognition receptor which has complex functions in innate immunity, extracellular matrix construction, and regulation of inflammation. Ongoing studies suggest that PTX3 may represent a novel marker of innate immunity-inflammatory reactions better representative of events involving tissues and in particular the vascular bed. At a basic research level, in the context of these studies the role of PTX3 in pathologies associated with aging will be investigated, including in particular its role in the pathogenesis of atherosclerosis.
Previous works suggest that PTX3 is present in atherosclerotic lesions and represent a novel marker for vascular pathology. Similar efforts will be conducted in models of rheumatoid arthritis. At a translational level, the possibility that PTX3 may serve as a useful marker for setting the set point of inflammation of higher levels in aged individuals will be explored. Moreover, the value of PTX3 as a novel prognostic marker in atherosclerotic disease in humans will be further investigated.
Mantovani A, Bonecchi R, Locati M.
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Bottazzi B, Garlanda C, Salvatori G, Jeannin P, Manfredi A, Mantovani A
Pentraxins as a key component of innate immunity
Curr. Opin Immunol. 18: 10-15, 2006.
Garlanda C., Bottazzi B., Bastone A., Mantovani A.,
Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility
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Garlanda C., Hirsch E., Bozza S., Salustri A., De Acetis M., Nota R., Maccagno A., Riva F., Bottazzi B., Peri G., Doni A., Vago L., Botto M., De Santis R., Carminati P., Siracusa G., Altruda A., Vecchi A., Romani L., Mantovani A.
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Nature 420: 182-186, 2002.