The role of the miR-17-92 cluster in macrophage driven innate immunity

Abstract

Research into miRNA, discovered in 1993, has exploded and revolutionized our understanding of molecular regulation in biological systems. MicroRNAs are now a well established as a regu- latory mechanism of many pathways and functions within cells of eukaryotic organisms, though much needs to be learnt about the intricacies of such regulation. In recent years, targeting this system of post-translational regulation has been a goal of many therapeutics, but requires much greater insight into how miRNA work, and the broadness of their activity.<br /> The innate immune system is critical for mounting an effective response against invading pathogens and protecting the host from damage. But being such a powerful system, unchecked it can wreak havoc on the host itself. While the innate immune system is tightly regulated by many mechanisms, further understanding could lead to major advances in therapeutics of autoim- mune diseases. As the miR-17-92 cluster has already been identified as a regulator of innate immune functions, and continued research in animal models is necessary for therapeutics to become a reality.<br /> This thesis focuses on the role and function of the miR-17-92 cluster within macrophages, which are a major component of the innate immune system. It highlights the complexity and often subtle nature of microRNA regulation in biological systems. It describes the generation of a mouse line with a myeloid-specific deletion of the miR-17-92 cluster is described, and shown that despite this deletion, there is no change both to the innate immune response of these mice, or to the TLR signalling cascade. It is postulated that while the miR-17-92 cluster affects innate immune signaling in some other cell types, it is unlikely to have a similar role in macrophages.