Community Research and Development Information Service - CORDIS


PHII Report Summary

Project ID: 669415
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - PHII (PTX3 in Humoral Innate Immunity)

Reporting period: 2015-09-01 to 2017-02-28

Summary of the context and overall objectives of the project

The general objective of our proposal is to explore unexpected vistas on humoral innate immunity, using as a molecular tool a novel molecule identified in our laboratory and called PTX3. In particular we proposed to test two related hypotheses:
1- First we aimed to test the hypothesis that matrix and microbe recognition are related functions of humoral molecules of the innate immune response. We use the soluble pattern recognition molecule PTX3 as a paradigm of humoral innate immunity molecules.
2- Second we aimed to test whether PTX3 and other elements of humoral innate immunity are essential components of cancer related inflammation.

The project has the general aim to identify new functional activities of humoral innate immunity molecules (using PTX3 as a paradigm) that could be translated to human clinics in the context of tissue damage and repair and in the context of cancer. In particular, the identification of new players involved in cancer related inflammation might open new therapeutic approaches for the immunotherapy of cancer.

We aim defining the role of PTX3 in tissue repair using different models of tissue damage, such as skin wound healing, chemically-induced liver damage, acid-induced lung damage. The study includes the characterization of molecular pathways involved in inducing PTX3 expression, the cellular sources of the protein, the localization of PTX3 in the damaged tissue during the evolution of lesions.
To investigate the molecular mechanisms underlying the involvement of PTX3 in tissue repair, we will define the interaction of PTX3 with the provisional matrix component fibrinogen and plasminogen, the consequences of these interactions and the role of pH acidification occurring during damage as a “switch on” signal for the tissue repair function of PTX3.
The second major aim is the characterization of PTX3 as an extrinsic oncosuppressor in mice by using different models of chemically induced mesenchymal and epithelial tumors. To investigate the molecular mechanisms underlying the involvement of PTX3 in cancer, we will investigate the role of PTX3 as regulator of complement activation and consequently, the effect on macrophage recruitment and polarization.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Results obtained in in vivo studies in PTX3-deficient mice are in agreement with our hypotheses and preliminary data, and indicate that PTX3 is involved in tissue repair and in modulating complement-dependent cancer-related inflammation (Figures 1-5).

In particular, activities performed showed that PTX3 plays a non-redundant role in tissue repair in a skin wound healing model (Figure 1) as well as in different models of tissue damage (i.e. chemically-induced sterile liver and lung injury). Under these conditions, macrophages and mesenchymal cells produced PTX3 in response to TLR activation and amplification by IL-1, localizing to the pericellular matrix of macrophages and mesenchymal-remodeling cells. In these conditions PTX3-deficiency was associated with increased clot formation, fibrin deposition and persistence, followed by increased collagen deposition (Figure 2). We found that PTX3, and in particular its N-terminal domain, interacts with fibrin and plasminogen, with higher affinity observed at acidic pH, a condition which occurs in damaged tissues (Figure 3). In vitro and in vivo studies demonstrated that by these interactions, PTX3 promoted remodelling of the fibrin-rich inflammatory matrix ensuring a normal tissue repair, thus providing a novel link between innate immunity, haemostasis and tissue repair.

Concerning PTX3 in cancer, activities performed showed that PTX3-deficiency in mice caused increased susceptibility to mesenchymal and epithelial carcinogenesis in the models of 3-Methylcholanthrene (3-MCA)-induced carcinogenesis, and 7,12-dimethylbenz [α] anthracene/terephthalic acid (DMBA/TPA)-induced skin carcinogenesis (Figure 4). In these models, PTX3 was produced by infiltrating macrophages and endothelial cells in response to IL-1.
PTX3-deficiency was associated with exacerbated cancer-related inflammation as revealed by enhanced macrophage infiltration in tumours, and higher pro-inflammatory cytokine production, angiogenesis, and complement C3 deposition and C5a levels. In the 3-MCA-induced cancer model, PTX3 regulated C3-deposition on sarcoma cells by interacting with and recruiting the negative regulator Factor H (Figure 5). Indeed, genetic inactivation of C3 reverted the increased susceptibility to 3-MCA-induced carcinogenesis and macrophage recruitment. These results indicate that in 3-MCA-induced sarcoma, unleashed complement activation and increased C5a production associated to PTX3-decifiency are likely responsible of exacerbated production of chemokines, which in turn cause increased recruitment of tumour promoting macrophages and favour M2-like polarization.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The results obtained in tissue repair models provide a novel link between innate immunity, haemostasis and tissue repair and open new therapeutic opportunities in the context of tissue damage associated with defective fibrinolysis and fibrosis.
Results obtained in cancer models unravel the involvement of humoral innate immunity, and in particular of complement, in cancer-related inflammation.
Since immunotherapy has an important impact on patients’ survival, the identification of new players of cancer-related inflammation has potential therapeutic implication in the context of immunotherapy of cancer.

Related information

Follow us on: RSS Facebook Twitter YouTube Managed by the EU Publications Office Top