Cecilia Garlanda Principal investigator View More
- AddressVia Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milano
- Telephone+39 0282245115
- Fax+39 0282245101
Our area of interest regards innate immunity and regulation of inflammatory responses. We investigate humoral innate immunity focusing on the long pentraxin PTX3 and complement, and regulation of inflammation focusing on IL-1R8/SIGIRR, a member of the family of Interleukin-1 Receptors. The methodological approaches used 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 information to human diseases.
Humoral innate immunity in the control of infections and inflammation regulation: The pentraxin PTX3
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 skin wound healing, and in cancer.
PTX3 is a soluble receptor of innate immunity, identified by the group directed by Alberto Mantovani in the ‘90s, and belonging to the family of pentraxins, as C-reactive protein. 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, using PTX3-deficient mice generated by the Laboratory. We pursue this effort by extending the list of pathogens controlled by PTX3 and by investigating the role of PTX3 in the regulation of inflammatory responses in the presence of pathogenic microorganisms or in condition of tissue damage, such as wound healing. 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. New lines of research on this molecule concern its involvement in tissue remodelling and tumor growth, as modulator of cancer-related inflammation and complement activation. In particular, we investigate the role of humoral innate immunity focusing on complement in cancer-related inflammation, in preclinical models and in human cancers. An effort shared with other groups of the Institute is focused on the transfer of PTX3 to the clinic, as potential diagnostic biomarker of inflammation, tissue damage and cancer.
Regulatory receptors of the Interleukin-1 system: The receptor IL-1R8/SIGIRR
The Laboratory also identified and characterized IL-1R8/SIGIRR, a member of the family of Interleukin-1Receptors/Toll Like Receptors. IL-1R8 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. Recently we demonstrated that IL-1R8 acts as a novel checkpoint in NK cells, tuning their maturation and functional activation against solid tumors, metastasis and viral infections.
IL-1R8 is a member of the family of receptors for interleukin-1, the prototypical inflammatory cytokine, and Toll Like Receptors (IL-1R/TLR), which are key recognition receptors for microorganisms and tissue damage. IL-1R8, identified by the group directed by Alberto Mantovani, differs from other family members, since it negatively regulates the activation of cell signalling mediated by other family members (such as IL-1R, IL-18R, TLR4, TLR9) and to act as receptor for the anti-inflammatory cytokine IL-37. The cascade of events that is activated after the recognition of cognate ligands by these receptors, leads to transcription of inflammation and immunity genes and 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. IL-1R8 represents a player of the negative control: it associates with molecules of the signalling pathway (such as MyD88 and IRAK) and reduces the activation of the transcription factor NF-kB, 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 IL-1R8 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. Recently, we described the function of IL-1R8 in NK cells, where this molecule acts as a checkpoint for IL-18-dependent NK cell maturation and activation, with important implications in the control of tumor growth, metastasis and viral infections.
Role of neutrophils in cancer
This line of research is coordinated by Sebastien Jaillon. The focus is the identification of the role of neutrophils in cancer using mouse models of carcinogenesis and genetic deficiency of neutrophils, and the investigation of the cross-talk between neutrophils and other leukocytes in the tumor microenvironment. Our group is also interested in studying the role of neutrophils in antitumor therapy efficacy (chemotherapy and immune checkpoint blockade) and in the clinical significance of tumor-associated neutrophils in patients.
Neutrophils have long been viewed essential for the elimination of extracellular pathogens and possessing a limited role in the orchestration of the immune response. This dogma has been challenged and neutrophils are now recognized as playing an important role in shaping both innate and adaptive responses. Neutrophils are a component of the tumor microenvironment (TME) but their role in cancer initiation and progression remains poorly understood. Indeed, controversial data were reported and neutrophils have been shown to promote both tumor progression and anti-cancer resistance. We are studying the role of neutrophils in carcinogenesis and antitumor immunity using a robust genetic approach of neutrophil deficiency (Csf3r-/- mice) and models of primary carcinogenesis. In particular, we recently discovered a novel neutrophil axis relevant for the control of mesenchymal carcinogenesis (A. Ponzetta et al., manuscript under revision). In human, neutrophils are now recognised as an important component of the TME of solid tumors including liver, lung, head and neck, kidney gastric and colorectal cancer (CRC). In general, neutrophil infiltration has been associated with worse prognosis. In CRC, the presence and significance of TAN have been the object of conflicting reports. These discrepant results may reflect different methodological approaches (e.g. different neutrophil markers, tissue microarray versus whole section immunohistochemistry, classification of patients). Recently, we defined a reliable methodology to assess TAN infiltration in CRC and to evaluate their clinical significance. We showed that CD66b was a neutrophil-specific marker to be used to quantify TANs in colorectal cancer biopsies and revealed that high TAN infiltration was associated with better response to 5-fluorouracil (5-FU)-based chemotherapy treatment. Therefore, TAN density may help identify patients likely to benefit from 5-FU-based chemotherapy.
Cecilia Garlanda Publications
Selected Publications: 20-25 publications listed in details with all the contributing authors, title of the papers, journal, dates. Hirsch E., Katanaev V. L., Garlanda C., Azzolino O., Pirola L., Silengo ...
Alessia Donato View More
Anna Rigatelli PhD student View More
Andrea Mariancini PhD student View More
Sarah Mapelli PhD, Postdoctoral Fellow View More
Silvia Carnevale PhD Student View More
Andrea Ponzetta PhD, Postdoctoral Fellow View More
Sebastien Jaillon PhD, Researcher/Assistant Professor View More
Nadia Polentarutti Technician View More
Chiara Perucchini Technician View More
Fabio Pasqualini Technician View More
Fatemeh Asgari PhD candidate View More
Sabrina Di Marco PhD student View More
Domenico Supino PhD Student View More
Elena Magrini PhD View More