Sepsis and rheumatoid arthritis are life-threatening diseases that represent a high cost to European countries' economies and a society characterized by an aging population and developing countries. Sepsis is due to a body's extreme response to an infection. It is the first cause of death in hospitalized patients, with an estimated 5 million deaths each year. There are no effective treatment protocols or strategies to deal with sepsis. Several approaches targeting known cellular pathways have failed. Rheumatoid arthritis, or RA, is an autoimmune and inflammatory disease. Briefly, the immune system attacks healthy cells by mistake, causing inflammation (painful swelling) in the body's affected parts. RA is a chronic condition that affects 1% of the population worldwide. Despite the existence of established guidelines, 66% of patients inadequately respond to the therapy.
Macrophages are cells of the innate immune system, which are specialized in sensing and responding to the presence of pathogens, causally involved in the pathogenesis of both sepsis and rheumatoid arthritis (RA). Their inflammatory phenotype is involved in the establishment and lethality of these diseases.
Our group discovered a novel and untapped DNA damage repair pathway involved in the transcriptional activation of macrophages' inflammation-related genes. The DNA damage repair machinery is potentially ripe for new approaches to inhibit the pro-inflammatory response. Indeed, we already proved that the inflammation is blunted in vivo by treating a mouse model of human sepsis with an existing therapeutic inhibitor of the DNA repair pathway. The systemic treatment massively protects 85% of mice from death by septic shock.
Thus, our proposed project is to test the large set of existing medical drugs targeting factors involved in DNA repair, so far used only or mainly in cancer therapies, to repurpose them to treat inflammatory immune disease. Our plan involves the first part using an in vitro strategy to test the efficacy of the inhibitors on different macrophage cell lines and a second part concerning the use of well-established mouse disease models for sepsis and RA.
