Role of cGAS in Fibroblasts Reticular Cells in Acute Intestinal Ischemia-Reperfusion Injury 2945

Abstract Description Circulating cell-free DNA levels increase during acute intestinal ischemia-reperfusion injury (AIIRI), which is associated with high mortality. Cyclic GMP-AMP synthase (cGAS) plays cell-specific roles in modulating organ immune homeostasis via sensing DNA. Fibroblasts Reticular Cells (FRC) modulate immune responses during health and diseases. However, the role of FRC-cGAS in AIIRI remains unclear. To understand the role of cGAS in AIIRI, we subjected C57BL/6 (WT) and cGAS-/- mice to AIIR (60min ischemia/4h reperfusion). Systemic, intestinal and pulmonary injuries were assessed by cytokine levels, histology, and neutrophil infiltration. As expected, AIIR induced systemic and organ injuries in WT mice by increasing IL-6 levels in the circulation, intestine, and lung, and elevating tissue damage and neutrophil infiltration in the intestine and lung. Knockout of cGAS alleviated AIIRI in the intestine and lung. To further investigate the role of FRC-cGAS in AIIRI, we isolated FRCs from the WT and cGAS-/- mice and treated them with Ht-DNA, a cGAS agonist. Ht-DNA treatment substantially increased the expression levels of cGAS downstream cytokines and signaling in WT-FRC. Furthermore, activation of cGAS signaling in WT FRC, but not cGAS-/- FRC, induced the release of chemokines, including CXCL1, CXCL2 and Rantes. These results suggest that FRC-cGAS may regulate immune responses during AIIRI. Future studies will examine FRC- cGAS-/- mice to understand the role of FRC-cGAS in AIIRI. Funding Sources NIH R01AI152044 (MeihongDeng:PI) Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)