Pathogenesis of Traumatic Brain Injury

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Macrophages play a central role in the immune response to traumatic brain injury, but their behavior cannot be accurately described using the traditional M1/M2 classification. Instead, macrophages in TBI exist along a continuum of activation states, shaped by the local microenvironment, metabolic conditions, and signals from damaged tissue.¹ These cells can simultaneously express inflammatory and reparative features, and their functions shift dynamically over time.²

Immediately after injury, macrophages respond to danger signals released from damaged neurons, glia, and blood‑derived factors. This early response includes the production of inflammatory cytokines, reactive oxygen species, and chemokines that help clear debris and recruit additional immune cells.³ However, single‑cell transcriptomic studies show that even in this early phase, macrophages display mixed phenotypes, combining inflammatory functions with genes involved in phagocytosis, lipid handling, and tissue remodeling.⁴ Their actions can be protective or harmful depending on the balance of signals in the injured brain.

As TBI progresses into subacute and chronic stages, macrophages continue to diversify. Some populations adopt pro‑repair functions, clearing apoptotic cells, supporting angiogenesis, and producing growth factors that aid tissue recovery.⁵ Others become dysregulated, contributing to chronic inflammation, fibrosis, glial‑scar remodeling, and long‑term neurodegeneration.⁶ Rather than switching from “M1 to M2,” macrophages in TBI transition through multiple intermediate states, each with distinct transcriptional signatures and functional roles. Therapeutic strategies now focus on targeting specific macrophage pathways—such as phagocytic efficiency, metabolic reprogramming, or cytokine production—rather than attempting to push cells into broad M1/M2 categories.¹⁻⁶

References

1. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–737.
Shows that macrophages exist along a spectrum of activation states rather than discrete M1/M2 categories.

2. Xue J et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40(2):274–288.
Provides foundational evidence that macrophage activation is multidimensional and context‑dependent.

3. Loane DJ, Kumar A. Microglia in the TBI brain: the good, the bad, and the dysregulated. Exp Neurol. 2016;275:316–327.
Describes early macrophage/microglial inflammatory responses after TBI and their dual protective/harmful roles.

4. Kim CC, Lanier LL. Beyond the transcriptome: single-cell immune profiling in health and disease. Nat Rev Immunol. 2021;21:341–356.
Shows how single‑cell sequencing reveals mixed and transitional macrophage states in CNS injury.

5. Shechter R et al. Recruitment of beneficial macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity. 2013;38(3):555–569.
Demonstrates reparative macrophage functions including phagocytosis, angiogenesis, and tissue remodeling.

6. Kroner A et al. TNF and increased intracellular iron alter macrophage polarization to a detrimental phenotype in spinal cord injury. Neuron. 2014;83(5):1098–1116.
Shows how dysregulated macrophage states contribute to chronic inflammation, fibrosis, and neurodegeneration.

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