Arvo building, auditorium F115, address: Lääkärinkatu 1.
Doctoral defence of MSc. Zuzet Martinez Cordova
The field of science of the dissertation is Immunology.
The opponent is Associated professor Kamran Ghoreschi (University of Tuebingen, Germany). Associated professor Marko Pesu acts as the custos.
The language of the dissertation defence is English.
FURIN anti-inflammatory function
Several proteins with essential functions in human biology are produced as non-functional molecules that require activation in order to perform their activity. This activation is mediated by other proteins called enzymes which have the ability to cleave at specific sites of the inactive proteins structure and produce functionally mature proteins. There are numerous families of enzymes, among them, Proprotein Convertases enzymes process a diverse type of proteins with roles in homeostasis and diseases. One of the member of Proprotein Convertase family is FURIN which is widely expressed in cells and tissues. Furthermore, a considerable number of investigations have demonstrated that FURIN activates various substrates with essential functions in microbial infectivity, as well as in disorders associated with dysregulation of the immune response such as autoimmunity, and cancer.
The immune system is a complex network of molecules, cells, tissues and organs that generate the adequate response to protect the body from harmful threats and defend against disease development. In order to facilitate the study, the immune system has been divided in two interconnected branches “the innate immunity” and “the adaptive immunity”. The innate immunity is the first line of defense from infection and comprises cells (eg. macrophages, neutrophils, dendritic cells) and mechanisms that provide a rapid, non-specific response. In contrast, the adaptive immunity is mediated by B cells and T cells and it is highly specific and adaptable.
FURIN has shown to be expressed in the activated cells of the innate (e.g macrophages) and adaptive immunity (e.g, T cells). Some studies have shown that FURIN regulates the adaptive immune response and exert a protective role against Rheumatoid arthritis. Furthermore, FURIN also activates highly pathogenic microbes such as bacillus anthracis and influenza A viruses. Remarkably, FURIN overexpression in several cancers have been correlated with bad prognosis. These observations have lead the scientific community to consider FURIN as a potential target for the development of novel therapeutics to treat autoimmune diseases, infection and cancer. Recently one vaccine that inhibit FURIN has entered the phase II of clinical trials for the treament of melanoma, ovarian cancer and colorectal cancer with liver metastasis.
The present thesis aimed to study the role of FURIN in innate immunity and skin cancer. Both, a mice model of endotoxemia where furin gene was specifically deleted in the cells of the innate immunity (macrophages and neutrophils) and a model of Mycobacterium marinum in zebrafish with inactive furinA gene; demonstrated enhanced innate immune responses. Briefly, mice with a deficiency of FURIN in macrophages displayed an intrinsic inflammatory state characterized by the production of the inflammatory molecule IL-1β. In addition, these mice showed an early mortality due to an aberrant production of pro-inflammatory cytokines after the induction of endotoxemia. Interestingly, in vitro studies performed in resting and activated FURIN deficient macrophages demonstrated high expression of pro-inflammatory genes and lower production of the anti-inflammatory molecule (TGF-β1). The production of two enzymes with pro-inflammatory roles (TACE and Caspase-1) was also increased in FURIN deficient macrophages.
In a model of Mycobacterium marinum in zebrafish with inactive furinA gene, mutants fish showed a reduction of furinA mRNA levels associated with low counts of innate immune cells (granulocytes) and elevated Th cell transcription factor expressions. In addition, silencing furin genes reduced the survival of M. marinum-infected zebrafish embryos. Mycobacterial infected furinA mutants exhibited a proinflammatory phenotype characterized by the elevated expression of pro-inflammatory genes. The enhanced innate immune response in the furinA mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. These observations support an anti-inflammatory role for FURIN in response to endotoxemia and Mycobaterium infection.
Remarkably, the deletion of furin gene in T cells but not in macrophages promotes an early aberrant immune response that lead to the formation of higher number of tumors (papilloma) in a mice model of squamous skin carcinoma. Although FURIN multifaceted functions highly recommend the enzyme as a potential therapeutic target in several disorders, our observations demonstrated the biological functions of FURIN are cell and tissue specific, hence the systematically use of FURIN inhibitors in therapeutics should be carefully evaluated before application.
The dissertation is published in the publication series of Acta Universitatis Tamperensis; 2269, Tampere University Press, Tampere 2017. The dissertation is also published in the e-series Acta Electronica Universitatis Tamperensis; 1770, Tampere University Press 2017.