Role of RNASET2 in innate immune response regulation

Numerous studies have highlighted the existence of enzymes that, besides presenting a conserved role, take part in different biological processes acquiring new functions. In particular, the T2 RNase family of enzymes is one of the most investigated group, which is involved not only in RNA regulation, but also performs additional functions, regardless of the catalytic activity. It has been recently observed that, through the continuous cross-talk between the cancer cells and the adjacent microenvironment and the activation of inflammatory response by inducing macrophages activation, the human protein RNASET2 is able to control the ovarian cancer malignancy. However, the details about the mechanisms by which T2 enzymes interact with immune system remain poorly defined. The medicinal leech Hirudo verbana is here proposed as a consolidated invertebrate model to shed light on these aspects. The results presented in this project reveal that both human and leech T2 RNases cause fibroplasia, connective tissue remodeling and macrophage recruitment in leeches. Moreover, in vivo and in vitro experiments proved that HvRNASET2, released by granulocytes after bacterial infection, is a candidate molecule for counteracting pathogens. In particular, it plays a dual role, inducing bacterial clustering to facilitate macrophage phagocytosis and promoting immunocompetent cells recognition. In conclusion, HvRNASET2 acts as an effector of innate immune response, to favore an efficient microbial pathogen elimination and an effective oncosuppressive activity. These studies, related to roles of T2 RNases in tissue remodeling, immune response modulation and antimicrobial activity, could be essential for developing new therapeutic application.