IL17RC signaling as a regulator of host- microbiota interactions and aortic neuroinflammation in atherosclerosis

PROJECT SUMMARY/ABSTRACT Cardiovascular diseases (CVD) are major cause of death worldwide. Various immune-mediated mechanisms are implicated in CVD pathogenesis. While microbiota regulates immunity, and altered microbiota composition had been linked to CVD; the mechanisms regulating host-microbiota interactions during atherosclerosis development and progression remain poorly understood. Cytokines are key mediators of inflammation and multicellular cross-talk in the aortic wall and emerging players in atherosclerosis. However, how cytokines regulate intestinal barrier and microbiota to distantly control atherosclerosis is unknown. Furthermore, the role of microbiota in the regulation of neuronal expansion and neuroinflammation in aorta has not been proposed. Interleukin (IL)17 had been implicated into the pathogenesis of various inflammatory diseases. Its role had been also investigated in atherosclerosis, however studies utilizing global IL17A or IL17R “gain- “or “loss-of-function” approaches came to conflicting conclusions, and cell type specific role of IL17 signaling had never been addressed. To determine if intestinal IL17RC signaling can distantly control atherosclerosis via microbiota- and immune-dependent mechanisms, we generated a new atherosclerosis-prone mouse model (Ldlr-/- Il17rcfl/fl VillinCre+). We found that IEC-specific ablation of IL17RC heightened intestinal inflammation, altered microbiota composition, and accelerate atherosclerosis accompanied by accumulation of activated immune cells and upregulation of neuronal signature in aortas of Ldlr-/- Il17rcfl/fl VillinCre+ mice, while these changes were abrogated by microbiota depletion. In this proposal, supported by a wealth of unexpected preliminary data, we will determine: 1) how IL17RC-dependent control of IEC metabolism and barrier function affects microbiota composition and function; and 2) determine the mechanistic link between IL17RC-dependent alteration of microbiota, metabolites and neuronal expansion and neuroinflammation in the aorta in atherosclerosis. We will use novel mouse models with cell type specific cytokine signaling inactivation, intestinal organoids, “gain-of- function” and “loss-of-function” experiments with microbiota and metabolites coupled with integrated array of cutting-edge transcriptomics, metabolomics, lipidomics, imaging, immunological and molecular biology analyses. Overall, these studies will allow to investigate novel role of IL17RC signaling in regulation of host-microbiota interactions and neuroinflammation in atherosclerosis and shed light on previously underappreciated cell type specific IL17 functions.