STING-dependent signaling in microglia or peripheral immune cells orchestrates the early inflammatory response and influences brain injury outcome

While originally identified as an antiviral pathway, recent work has implicated cyclic GMP-AMP-synthase-Stimulator of Interferon Genes (cGAS-STING) signaling as playing a critical role in the neuroinflammatory response to traumatic brain injury (TBI). STING activation results in a robust inflammatory response characterized by the production of inflammatory cytokines called interferons, as well as hundreds of interferon stimulated genes (ISGs). Global knockout (KO) mice inhibiting this pathway display neuroprotection with evidence that this pathway is active days after injury; yet, the early neuroinflammatory events stimulated by STING signaling remain understudied. Furthermore, the source of STING signaling during brain injury is unknown. Using a murine controlled cortical impact (CCI) model of TBI, we investigated the peripheral immune and microglial response to injury utilizing male chimeric and conditional STING KO animals, respectively. We demonstrate that peripheral and microglial STING signaling contribute to negative outcomes in cortical lesion volume, cell death, and functional outcomes post injury. A reduction in overall peripheral immune cell and neutrophil infiltration at the injury site is STING dependent in these models at 24 hours. Transcriptomic analysis at 2 hours, when STING is active, reveals that microglia drive an early, distinct transcriptional program to elicit proinflammatory genes including interleukin 1-beta (IL-1β), which is lost in conditional knockout mice. The upregulation of alternative innate immune pathways also occurs after injury in these animals, which supports a complex relationship between brain-resident and peripheral immune cells to coordinate the proinflammatory response and immune cell influx to damaged tissue after injury. Significance Statement The innate immune STING pathway triggers harmful neuroinflammation after traumatic brain injury with support from human and preclinical models indicating that this pathway is active hours to days after injury. Our findings in a preclinical cortical contusion model suggest that STING signaling specifically from peripheral immune cells or microglia drive this process to affect injury outcome. Activation of STING in microglia as early as 2 hours post-injury drives a distinct transcriptional program that influences neutrophil and peripheral immune cell influx, which dictates injury outcomes. These findings shed light on the acute temporal changes in a cell-type specific manner where innate immunity drives subsequent events that affect secondary injury processes after insult.