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

作者：Lauren E. Fritsch, Colin Kelly, John W. Leonard, Caroline de Jager, Xiaoran Wei, Samantha Brindley, Elizabeth A. Harris, Alexandra M. Kaloss, Nicole DeFoor, Swagatika Paul, Hannah O’Malley, Jing Ju, Michelle L. Olsen, Michelle H. Theus, Alicia M. Pickrell · 发表于：Journal of Neuroscience · 年份：2024 · DOI：10.1523/jneurosci.0191-23.2024 · 被引用次数：18 · 研究领域：interferon and immune responses、Immune Response and Inflammation、S100 Proteins and Annexins

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 knock...