STING-Dependent Signaling in Microglia or Peripheral Immune Cells Orchestrates the Early Inflammatory Response and Influences Brain Injury Outcome.
| Title: | STING-Dependent Signaling in Microglia or Peripheral Immune Cells Orchestrates the Early Inflammatory Response and Influences Brain Injury Outcome. |
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| Authors: | Fritsch LE; Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Roanoke, Virginia 24016 alicia.pickrell@vt.edu.; Kelly C; Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Roanoke, Virginia 24016 alicia.pickrell@vt.edu.; Leonard J; Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; de Jager C; Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Roanoke, Virginia 24016.; Wei X; Biomedical and Veterinary Sciences Graduate Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; Brindley S; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; Harris EA; Biomedical and Veterinary Sciences Graduate Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; Kaloss AM; Biomedical and Veterinary Sciences Graduate Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; DeFoor N; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; Paul S; Biomedical and Veterinary Sciences Graduate Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; O'Malley H; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; Ju J; Biomedical and Veterinary Sciences Graduate Program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; Olsen ML; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; Theus MH; Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.; Pickrell AM; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 alicia.pickrell@vt.edu. |
| Source: | The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2024 Mar 20; Vol. 44 (12). Date of Electronic Publication: 2024 Mar 20. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Electronic Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington, DC : Society for Neuroscience; Original Publication: [Baltimore, Md.] : The Society, c1981- |
| MeSH Terms: | Brain Injuries, Traumatic*/pathology ; Microglia*/metabolism; Cytokines/metabolism ; Interferons/metabolism ; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Signal Transduction ; STING Protein |
| Abstract: | While originally identified as an antiviral pathway, recent work has implicated that cyclic GMP-AMP-synthase-Stimulator of Interferon Genes (cGAS-STING) signaling is 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 knock-out (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 postinjury. A reduction in overall peripheral immune cell and neutrophil infiltration at the injury site is STING dependent in these models at 24 h. Transcriptomic analysis at 2 h, when STING is active, reveals that microglia drive an early, distinct transcriptional program to elicit proinflammatory genes including interleukin 1-β (IL-1β), which is lost in conditional knock-out 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.; (Copyright © 2024 the authors.) |
| Competing Interests: | The authors declare no competing financial interests. |
| Grant Information: | R35 GM142368 United States GM NIGMS NIH HHS |
| Contributed Indexing: | Keywords: STING; brain injury; innate immunity; microglia; neuroinflammation; neutrophils |
| Substance Nomenclature: | 0 (Cytokines); 9008-11-1 (Interferons); 0 (Sting1 protein, mouse); 0 (STING Protein) |
| Entry Date(s): | Date Created: 20240215 Date Completed: 20240326 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10957216 |
| DOI: | 10.1523/JNEUROSCI.0191-23.2024 |
| PMID: | 38360749 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural