STING Promotes Macrophage-Mediated Resolution of Inflammation Through IFNβ Production

Introduction: The engulfment of apoptotic leukocytes (efferocytosis) by macrophages during the resolution of inflammation is essential for tissue homeostasis and results in macrophage reprogramming/immune-silencing. Previously, a distinct subtype of resolution-phase macrophages characterized by decreased expression of CD11b, arrest of efferocytosis (satiation) and enhanced reprograming into pro-resolving and anti-fibrotic phenotypes was identified. These satiated macrophages display increased production and secretion of the immunomodulatory cytokine IFNβ.

Materials and Methods: To elucidate the role of the intracellular adaptor protein stimulator of IFN genes (STING) in macrophage production of IFNβ and its consequences, satiated macrophages were sorted from zymosan-A induced peritonitis and the activation of the STING pathway in these macrophages was examined. In addition, resolution phase macrophages were recovered from WT and STING^-/- mice, and analyzed for their cytokine production, efferocytosis, and reprogrammed phenotype using flow cytometry, WB, ELISA and fluorescent microscopy.

Results and Discussion: Here, we show that satiated macrophages display increased activation of STING, Tank binding kinase (TBK) 1, and IRF3 concomitantly with increased expression of IFNβ and ISG15. However, IFNβ levels were reduced in peritoneal exudates from STING^-/- mice. Moreover, activation of the STING-IFNβ pathway, macrophage efferocytosis, reprogramming and responsiveness to apoptotic cells were all diminished in STING^-/- resolution phase macrophages, and rescued, at least in part, by exogenous IFNβ.

Conclusions: Thus, our findings indicate that STING is an essential mediator in driving IFNβ expression and secretion by satiated macrophages and consequently in shaping macrophage function and phenotype changes during resolving inflammation.