Loss of Adenosine Deaminase Acting on RNA 1 Induces Panoptosis and Immune Response in Ulcerative Colitis Gut Mucosa

Abstract

The gut virome is a complex community that exists in equilibrium with the host. Disruptions of this balance could drive the development of inflammatory diseases, such as inflammatory bowel disease (IBD). RNA editing, particularly A-to-I editing by ADAR1, prevents the excessive immune response to viral double strand (ds) RNA. Failure of RNA editing may sustain inflammation and this study explore the role of ADAR1 in IBD. ADAR1 was analyzed in IBD patients and healthy controls (CTR) using western blotting and qPCR. Colonic epithelial cells (HCEC-1CT), ex vivo organ cultures, and colonic organoids were treated poly I:C after ADAR1 silencing with an antisense oligonucleotide (AS). Inflammatory pathways and PANoptosome were measured by western blotting, flow cytometry, and ELISA. The role of ADAR1 was also studied in DSS-colitis model. ADAR1 was significantly reduced in the inflamed epithelium of ulcerative colitis (UC) gut samples. ADAR1 silencing in HCEC-1CT, ex vivo organ cultures or colonic organoids strongly increases the immune response to poly I:C and leads to activation of inflammatory pathways and PANoptosis. Inhibition of gut ADAR1 expression during DSS-colitis exacerbated gut inflammation. JAK inhibition or AhR activation mitigated the immune response that follows ADAR1 silencing. These data suggest that ADAR1 could be involved in IBD inflammation.