SAVI mutations in the adapter protein STING lead to intestinal inflammation and fibrosis in mice
Liraz Shmuel-Galia | Fitzgerald Lab | Crohn’s and Colitis Foundation of America Research Award
SAVI mutations in the adapter protein STING lead to intestinal inflammation and fibrosis in mice
Summary: Studies in IBD patients and in mouse models have implicated STING activation as a regulator of intestinal inflammation. Murine studies in STING loss of function genetic models, have revealed both protective and detrimental roles for this pathway in the gut. In this study, we aim to explore the molecular mechanisms and consequences of STING mediating intestinal inflammation. Using a mouse model harboring a gain of function mutation in the gene encoding STING, Tmem173, we generated a new model of spontaneous colitis without chemical disruption. Asparagine to Serine (N153s) gain of function mutation, corresponds to the human N154s mutation in STING was recently reported in patients of STING-associated Vasculopathy with Onset in Infancy (SAVI)[1-5]. Patients suffering from SAVI exhibit an elevated Interferon Stimulated Gene (ISG) expression signature in peripheral cells as well as respiratory failure, skin rash and pulmonary fibrosis.
Here we report that N153s mice also exhibit profound intestinal inflammation. We found that WT mice express low level of STING protein in the colon and that STING expression in the N153s mice increased over time and correlated with the onset of disease progression. Measurement of STING levels in colon tissue biopsies from IBD patients revealed stabilization of STING in areas of the colon with active disease compared to adjacent unaffected tissue, emphasising the potential link of STING expression in the gut to intestinal inflammation . Antibiotic treatment as well as replacement of the microbiota by WT fecal microbiota transplantation (FMT) alleviates intestinal inflammation and reduces protein levels of STING in the N153s mice colon, highlighting the microbiome as an essential contributing factor to disease.
This proposal aims to build on these findings and define the molecular and cellular basis of chronic intestinal inflammation due to constitutive activation of STING. Specifically, we aim to: (1) assess dysbiosis and its effect on intestinal inflammation in N153s mice and (2) identify the cellular and molecular mechanism(s) initiating dysbiosis and colitis in N153s mice. Completion of this study will provide a new framework for understanding the progression of IBD. Furthermore, delineating STING function in the development of IBD may identify new therapeutic targets and improve treatment options for IBD and patient quality of life.
