The BiST of Burden: Harnessing biased STING agonists to enhance the resolution of inflammation and wound repair and limit tissue fibrosis 9003

Abstract Description Stimulator of IFN Genes (STING) is a cytosolic DNA sensor that plays a central role in host protection against pathogens upon binding DNA-derived ligands. STING primarily controls the transcription of type I interferons (IFNs) and pro-inflammatory cytokines. Notably, STING can be tuned pharmacologically to mitigate human immune pathologies. DMXAA is a pharmacological activator of murine STING that induces IFN-β and its affected genes. Here, we report that macrophages from DMXAA-treated mice engulfed significantly higher numbers of apoptotic cells ex vivo, and exhibited enhanced reprogramming reflected by an increased IL-10 and reduced inflammatory cytokine secretion upon LPS exposure. Macrophage reprogramming was significantly hampered in STING and IFN-β -deficient macrophages. Furthermore, we used virtual docking and batch screening to identify biased STING agonists (BiSTs) that enhanced IL-10 and IFN-β production by splenocytes while inhibiting TNFα. One of these compounds, termed BiST 2.1, also induced the murine STING pathway in vivo and in human macrophages. Finally, we found BiST 2.1 to enhance wound repair by mouse embryonic fibroblasts and promote the resolution of liver fibrosis induced by CCl4. Thus, our findings indicate that STING can be harnessed to drive IFN-β-mediated IL-10 secretion by resolution phase macrophages and consequently shape macrophage and fibroblast function to enhance the resolution of inflammation and treat fibrotic disorders. Funding Sources Israel Science Foundation, No 1207/22 Israel Innovation Authority Topic Categories Translational and Interventional Immunology (TI)