Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift
Open accessAbstract
Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with a considerable socioeconomic burden. Heterogeneity of pathoanatomical subtypes and diversity in the pathogenesis and extent of injury contribute to differences in the course and outcome of TBI. Following the primary injury, extensive and lasting damage is sustained through a complex cascade of events referred to as "secondary injury." Neuroinflammation is proposed as an important manipulable aspect of secondary injury in animal and human studies. Because neuroinflammation can be detrimental or beneficial, before developing immunomodulatory therapies, it is necessary to better understand the timing and complexity of the immune responses that follow TBI. With a rapidly increasing body of literature, there is a need for a clear summary of TBI neuroimmunology. This review presents our current understanding of the immune response to TBI in a chronological and compartment-based manner, highlighting early changes in gene expression and initial signaling pathways that lead to activation of innate and adaptive immunity. Based on recent advances in our understanding of innate immune cell activation, we propose a new paradigm to study innate immune cells following TBI that moves away from the existing M1/M2 classification of activation states toward a stimulus- and disease-specific understanding of polarization state based on transcriptomic and proteomic profiling.
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This alarmin detection triggers a rapid inflammatory response characterized by inflammasome assembly, nuclear factor-κβ signaling, resident immune cell activation, cytokine and chemokine production, and recruitment of peripheral myelomonocytic cells.
“This, in turn, triggers a rapid inflammatory response characterized by inflammasome assembly, nuclear factor-κβ signaling, resident immune cell activation, cytokine and chemokine production (such as IL-6, TNFα, CXCL1, CXCL2, and CCL2), and recruitment of peripheral myelomonocytic cells, among others (Fig. 4) (130).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [130]
TBI and associated CNS vascular damage is a type of sterile injury.
“TBI and the associated CNS vascular damage is a type of sterile injury [recently reviewed in (130)].”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [130]
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In vivo dynamics of innate immune sentinels in the CNS
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Self-citationChiaretti, A., Antonelli, A., Mastrangelo, A., Pezzotti, P., Tortorolo, L., Tosi, F., & Genovese, O. (2008) · Journal of Neurotrauma · doi:10.1089/neu.2007.0405 · Cited by 108 · see citing works
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Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury
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Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner
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The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
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Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury
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The role of the brain renin-angiotensin system (RAS) in mild traumatic brain injury (TBI)
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Xie, M., Wang, T., Feng, J., Ma, D., Feng, L., & Hao, Y. (2025) · Current Neuropharmacology · doi:10.2174/1570159x23666250225091729 · Cited by 7 · see citing works
- Authors
- Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J.
- Affiliations
- National Institutes of Health (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- McGavern, Dorian B.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 95
- Issue
- 6
- Pages
- 1246-1265
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5678753
- OpenAlex
- W2754554955
- Cited by
- 799
- References
- 270
- Citations by year
- 2026: 76 · 2025: 87 · 2024: 83 · 2023: 99 · 2022: 130 · 2021: 124 · 2020: 96 · 2019: 62 · 2018: 39 · 2017: 3
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH
- NIA (RF1AG051506)
- NINDS (1R21HD086385)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, neuroimmunology, neuroinflammation, secondary injury, innate immunity, adaptive immunity, immune cell polarization, gene expression profiling, proteomic profiling, immune signaling pathways, immunomodulatory therapy
- MeSH terms
- Brain Injuries, Traumatic, Animals, Astrocytes, Humans, Immunity, Innate, Inflammation, Microglia, Models, Immunological, Proteomics, Adaptive Immunity, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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