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Cover ArticleResearch Articles, Neurobiology of Disease

Amplified Gliosis and Interferon-Associated Inflammation in the Aging Brain following Diffuse Traumatic Brain Injury

Lynde M. Wangler, Chelsea E. Bray, Jonathan M. Packer, Zoe M. Tapp, Amara C. Davis, Shane M. O'Neil, Kara Baetz, Michelle Ouviña, Mollie Witzel and Jonathan P. Godbout
Journal of Neuroscience 30 November 2022, 42 (48) 9082-9096; DOI: https://doi.org/10.1523/JNEUROSCI.1377-22.2022
Lynde M. Wangler
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
2Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
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Chelsea E. Bray
2Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
4College of Medicine, The Ohio State University, Columbus, Ohio 43210
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Jonathan M. Packer
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
2Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
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Zoe M. Tapp
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
2Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
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Amara C. Davis
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
2Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
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Shane M. O'Neil
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
2Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
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Kara Baetz
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
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Michelle Ouviña
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
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Mollie Witzel
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
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Jonathan P. Godbout
1Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
2Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210
3Chronic Brain Injury Program, The Ohio State University, Columbus, Ohio 43210
4College of Medicine, The Ohio State University, Columbus, Ohio 43210
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Abstract

Traumatic brain injury (TBI) is associated with chronic psychiatric complications and increased risk for development of neurodegenerative pathology. Aged individuals account for most TBI-related hospitalizations and deaths. Nonetheless, neurobiological mechanisms that underlie worsened functional outcomes after TBI in the elderly remain unclear. Therefore, this study aimed to identify pathways that govern differential responses to TBI with age. Here, adult (2 months of age) and aged (16–18 months of age) male C57BL/6 mice were subjected to diffuse brain injury (midline fluid percussion), and cognition, gliosis, and neuroinflammation were determined 7 or 30 d postinjury (dpi). Cognitive impairment was evident 7 dpi, independent of age. There was enhanced morphologic restructuring of microglia and astrocytes 7 dpi in the cortex and hippocampus of aged mice compared with adults. Transcriptional analysis revealed robust age-dependent amplification of cytokine/chemokine, complement, innate immune, and interferon-associated inflammatory gene expression in the cortex 7 dpi. Ingenuity pathway analysis of the transcriptional data showed that type I interferon (IFN) signaling was significantly enhanced in the aged brain after TBI compared with adults. Age prolonged inflammatory signaling and microgliosis 30 dpi with an increased presence of rod microglia. Based on these results, a STING (stimulator of interferon genes) agonist, DMXAA, was used to determine whether augmenting IFN signaling worsened cortical inflammation and gliosis after TBI. DMXAA-treated Adult-TBI mice showed comparable expression of myriad genes that were overexpressed in the cortex of Aged-TBI mice, including Irf7, Clec7a, Cxcl10, and Ccl5. Overall, diffuse TBI promoted amplified IFN signaling in aged mice, resulting in extended inflammation and gliosis.

SIGNIFICANCE STATEMENT Elderly individuals are at higher risk of complications following traumatic brain injury (TBI). Individuals >70 years old have the highest rates of TBI-related hospitalization, neurodegenerative pathology, and death. Although inflammation has been linked with poor outcomes in aging, the specific biological pathways driving worsened outcomes after TBI in aging remain undefined. In this study, we identify amplified interferon-associated inflammation and gliosis in aged mice following TBI that was associated with persistent inflammatory gene expression and microglial morphologic diversity 30 dpi. STING (stimulator of interferon genes) agonist DMXAA was used to demonstrate a causal link between augmented interferon signaling and worsened neuroinflammation after TBI. Therefore, interferon signaling may represent a therapeutic target to reduce inflammation-associated complications following TBI.

  • aging
  • interferon
  • microglia
  • neuroinflammation
  • STING
  • traumatic brain injury

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The Journal of Neuroscience: 42 (48)
Journal of Neuroscience
Vol. 42, Issue 48
30 Nov 2022
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Amplified Gliosis and Interferon-Associated Inflammation in the Aging Brain following Diffuse Traumatic Brain Injury
Lynde M. Wangler, Chelsea E. Bray, Jonathan M. Packer, Zoe M. Tapp, Amara C. Davis, Shane M. O'Neil, Kara Baetz, Michelle Ouviña, Mollie Witzel, Jonathan P. Godbout
Journal of Neuroscience 30 November 2022, 42 (48) 9082-9096; DOI: 10.1523/JNEUROSCI.1377-22.2022

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Amplified Gliosis and Interferon-Associated Inflammation in the Aging Brain following Diffuse Traumatic Brain Injury
Lynde M. Wangler, Chelsea E. Bray, Jonathan M. Packer, Zoe M. Tapp, Amara C. Davis, Shane M. O'Neil, Kara Baetz, Michelle Ouviña, Mollie Witzel, Jonathan P. Godbout
Journal of Neuroscience 30 November 2022, 42 (48) 9082-9096; DOI: 10.1523/JNEUROSCI.1377-22.2022
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Keywords

  • aging
  • interferon
  • microglia
  • neuroinflammation
  • STING
  • traumatic brain injury

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