Resumen de Trex1 and Nbs1 as Regulators of the Macrophage Inflammatory Response
Selma Patrícia Pereira Lopes
Trex1 is an exonuclease that was first identified in mammal cells and due to its role in DNA metabolism was conjectured to have a role in DNA damage repair and cancer. It was unexpected to find that Trex1-/- mice generated a few years later did not present increased cancer incidence but an inflammatory myocarditis that lead to premature death. Furthermore, TREX1 mutations were later associated to a number of different diseases that presented deregulation of the immune system, such as, SLE but also neurological defects in AGS. Nbs1 is a 95kDa protein and was first identified to it its interaction with Mre11 and Rad50 (MRE11 complex). This complex is important for DSB detection and repair and has been conserved overall the species. The genomic region encoding Nbs1 was previous noted to be mutated in NBS patients. These patients are characterised with immunodeficiency, neural defects and increased cancer incidence. This Thesis comprises three main parts. The first part characterises Trex1 as promoter and describes its induction upon IFN-? stimulation. The second part describes how and to what extent the lack of Trex1 in macrophages affects its function upon TLR stimulation and further explains molecular mechanisms behind autoimmunity in the absence of Trex1 function. Finally, the last part, focuses primarily on Nbs1, assesses the importance of a fully functional Nbs1 in macrophage function and on immune response in vivo. Taking the previous stated into account it can be concluded that Trex1 and Nbs1 are cornerstone proteins of macrophage pro-inflammatory function and although the roles of these proteins in macrophages are different, in essence, they both are indispensably crucial for DNA metabolism. This further suggests that the tight regulation of the amounts of free DNA in macrophages is important in the pro-inflammatory but not in anti-inflammatory response and that both Nbs1 and Trex1 are indispensable for macrophage inflammatory regulation.
