RIG-I-like receptor regulation of pulmonary inflammation and homeostasis

PROJECT SUMMARY Stringent regulation of inflammation during infectious and non-infectious diseases is critical for limiting tissue pathology while promoting disease resolution. The dead-box helicase family members known as retinoic acid- inducible gene I-like receptors (RIG-I-like receptors, RLRs) play a critical role in recognizing self and non-self nucleic acids in the cytosol of host cells. Dysregulation of RLRs and their downstream interferon (IFN) and inflammatory signaling cascade can manifest as autoimmunity or as defects in antimicrobial responses. Despite the critical importance of RLRs, the function of these receptors and their associated molecular pathways in different cell types, remains an important gap in our understanding of tissue homeostasis versus diseased states. As an independent investigator, my studies now focus on how emerging non-canonical functions of RLRs and IFN regulate inflammation in the context of pulmonary pathogenesis and immune cell programming, two critical areas in which better understanding of RLR-associated signaling could lead to new strategies for treating infectious and non-infectious inflammatory diseases. Our preliminary studies have found that atypical induction of the RLR RIG-I using a synthetic agonist leads to activation of immune cell programming genes rather than IFN induction. Moreover, we have identified new roles for type III IFN (IFN) in pulmonary tissue repair following pathogen-induced damage. My research program can be defined with three thematic goals: 1) elucidate how RLRs and IFN pathways contribute to tissue homeostasis, 2) determine whether RLR and IFN pathways are differentially activated in a strategically-selected set of cell types in damaged vs adjacent tissues, and 3) determine the distinct contributions of RLR and IFN in controlling non-infectious or infection-mediated inflammation and resolution. We have developed first-of-their-kind mouse models to eliminate expression of the RLRs RIG-I, MDA5, and their downstream signaling adapter MAVS, as well as type I and type III IFN signaling pathways in temporal and cell-specific fashions. These tools will allow us to use cutting edge high-parameter spectral cytometry, along with spatial transcriptomics, to define the most relevant inflammatory pathways deployed by individual cell types in the context of their natural tissue microenvironment. Ultimately, our studies will improve understanding of cell-intrinsic regulation of nucleic acid sensing pathways, and will provide strategies for differentially targeting each pathway to maximize therapeutic benefit while minimizing adverse side effects.