Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis

Patho-mechanistic origins and disease dynamics of ulcerative colitis are still poorly understood. The actin crosslinker Filamin A (FLNA) impacts cellular responses through interaction with numerous, cytosolic proteins. FLNA exists in two forms that differ only in a single amino acid: genome-encoded FLNAQ, and FLNAR - generated by post-transcriptional A-to-I editing. In the intestinal tract, FLNA is edited in fibroblasts, smooth muscle- and endothelial cells and we identified the FLNA editing status as a key determinant of colitis severity. FLNA editing was highest in healthy colons, and reduced during acute murine and human colitis. Mice that exclusively express edited FLNAR and do not downregulate editing upon challenge were highly resistant to DSS-induced colitis, whereas fully unedited FLNAQ animals developed severe inflammation. While the genetic induction of FLNA editing influenced the transcriptional states of intestinal structural cells and microbiome composition, we found that edited FLNAR exerts protection specifically via its influence on myeloid immune cells, which are not edited under physiological conditions. The introduction of a fixed FLNAR editing state, did not hamper normal cell migration but reduced macrophage inflammation and rendered neutrophils less prone to NETosis. We thus conclude that loss of FLNA editing correlates with colitis severity and targeted FLNA editing of myeloid cells might serve as novel therapeutic approach in intestinal inflammation. Overall design: FACS-sorted cells from DSS-colitis induced 8-10-week-old mice. Samples are defined by (1) tissue-of-origin, (2) cell type, (3) Duration of DSS-treatment. A variable number of biological replicates are included.