Il22 regulatory elements shape inflammatory responses in Imiquimod-induced psoriasis 2258410

Abstract

Abstract Introduction IL22 is a type III cytokine produced by innate and adaptive lymphocytes that is essential for maintaining tissue homeostasis and establishing a defense against extracellular pathogens. Dysregulation of IL22 contributes to the development of immune-mediated diseases such as psoriasis. Methods We identified two conserved enhancer elements (E22-1 and E22-2) for Il22 by a CRISPR interference (CRISPRi) screen. We additionally identified a superenhancer for Il22 (SE22) using H2K27ac chromatin immunoprecipitation sequencing (ChIP-Seq) of human tonsillar ILC3s, which is also conserved in mouse. Results Knockout mice for SE22 or E22-1 resulted in partial loss of IL-22 expression in ILC3s as well as αβ T, iNKT, and γδ T cells. In contrast, deletion of E22-2 impaired IL-22 expression only in ILC3s. We demonstrate that the enhancer elements are bound by the RUNX family and RORC transcription factors in a site dependent manner resulting in cell type specific control of IL22 expression in ILC3s by E22-2. We further demonstrate that the partial loss of IL22 in each of the knockout strains protects from development of imiquimod induced psoriasis through a decrease in Il22 but not Il17a or Il17f. Conclusion Further characterization of cis-regulatory elements of Il22 may provide key targets for epigenetic therapy to treat autoimmune disease. Funding Source NIH 5R01AI134035 and NIH 5T32AI165391 Topic Categories Cytokines and Chemokines and their Receptors (CCR)