A to I editing has been shown to be protective in experimental models of colitis, by yet unknown mechanism(s). We aim to elucidate how A to I editing impacts experimental colitis. Using a chemically-induced colitis mouse model, transcriptomics, tests for gut permeability, immunohistochemistry and bone marrow transplant approaches we want to better understand how, during colitis, RNA editing impacts on epithelial cell barrier function and on immune response driven pathology. In addition we will assess how RNA editing influences microbiome composition and evaluate the impact of A to I editing-driven microbiome alterations in colitis.
In the gut, host and microbiota constantly communicate, and RNA moieties such as microRNAs (miRNAs) mediate such crosstalk. MiRNAs are small non-coding RNAs that can bind to target mRNAs, leading to translation inhibition or transcript degradation. Strikingly, the expression of several miRNAs is altered in IBDs and other chronic inflammatory diseases. Furthermore, depletion of particular fecal miRNAs causes shifts in microbiota composition and alters mouse susceptibility to colitis in a microbiota-dependent fashion. We are studying how luminal miRNAs and miRNA editing in the large intestine impact gut microbiome composition and function under both normal and inflammatory conditions.
The ADAR2 edtitase accounts for most editing sites within transcriptomic coding regions. Sofar, ADAR2 recoding has mostly been studied in the nervous system, due to its high expression levels and its vital function in the brain. Interestingly the lung shows substantial ADAR2 expression too, which seem to be at least partially derived from high ADAR2 levels found in lung-tissue resident alveolar macrophages (AM). However, nothing is known about potential ADAR2 targets or functions in the lung or in AM.
AM are at the front line of immune defense in the lung and thus are highly specialized to maintain lung homeostasis upon constant exposure to the environment. As such, they have a strong phagocytic capacity and constantly patrol alveoli to immediately remove potentially harmful microbes, particles and apoptotic material. Using transcriptomics and editing analysis in primary mouse alveolar macrophages we work on the identification of cell-type and/or condition specific ADAR2 targets in AM. As ADAR2 is important for Filamin A Q to R editing, and Filamin A is a crucial actin-binding protein, we will further investigate phagocytosis and cell migration upon ADAR2 deficiency. This in vitro approach is complemented by the phenotypical characterization of ADAR2 deficient mice in murine COVID19 and pneumococcal pneumonia models, clinically relevant lung infection models in vivo.