Harnessing the STING-IFNβ axis to enhance the resolution of inflammation

Stimulator of IFN Genes (STING) is a cytosolic DNA sensor that plays a central role in host protection against pathogens upon binding of DNA-derived ligands. STING primarily acts by controlling the transcription of type I interferons (IFNs) and pro-inflammatory cytokines. Notably, STING can be inhibited or activated pharmacologically to control STING-associated pathologies. 5, 6-Dimethylxanthenone-4-acetic Acid (DMXAA) is a pharmacological activator of murine STING that induces IFN-β and its affected genes. We used WT, STING-/-, and IFN-b-/- mice treated with DMXAA to determine whether modulation of STING activity during the resolution phase of inflammation can affect macrophage function. In addition, we examined the regulatory function of novel small molecules that were found to bind murine STING in silico. We found 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-b-deficient macrophages. Furthermore, we found that two of the putative STING modulators inhibited DMXAA-induced TNF-α and IL-10 secretion. Another two compounds selectively promoted IL-10, while inhibiting TNF-α secretion under these settings. The later compounds also modulated STING signaling in a selective manner. Thus, our findings indicate that STING can be harnessed to drive IFNβ-mediated IL-10 secretion by resolution phase macrophages and consequently shape macrophage function to enhance the resolution of inflammation and treat autoimmune, inflammatory, and fibrotic disorders.