Regulation of Alveolar Macrophage Functions by ADAR2 editing

The lung is vital for gas exchange and constantly exposed to the environment. Thus, lung immunity has to be tightly controlled to ensure the effective clearance of potentially harmful pathogens while avoiding inflammation induced tissue damage. Alveolar macrophages are key immune cells in the lung and critical in tailoring inflammatory responses during infection. Compared to other macrophages and immune cell types, AMs express exclusively high levels of the adenosine deaminase acting on RNA-2 (ADAR2) an Enzyme that facilitates a specific mRNA modification, namely adenosine (A) to inosine (I) editing. A to I editing is known to modulate cellular responses, but its exact role in AMs has not been studied so far. Considering the specific functional properties of AMs and their particularly high levels of ADAR2, we hypothesized that ADAR2 mediated A to I editing in AMs specifically influences their responses to pathogenic stimuli. Using novel sequencing-, screening and high resolution microscopy approaches together with genetically modified AMs (lacking ADAR2), we will in this project dissect the exact role of editing in AMs. We will unveil novel mechanistic pathways which may in the future be exploited for the development of novel therapeutic approaches to combat hyperinflammation. In addition, this work will contribute to the better understanding of pathological mechanisms which drive lung damage during bacterial and viral pneumonia.