White matter damage after traumatic brain injury: A role for damage associated molecular patterns

Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and long-term morbidity worldwide. Despite decades of pre-clinical investigation, therapeutic strategies focused on acute neuroprotection failed to improve TBI outcomes. This lack of translational success has necessitated a reassessment of the optimal targets for intervention, including a heightened focus on secondary injury mechanisms. Chronic immune activation correlates with progressive neurodegeneration for decades after TBI; however, significant challenges remain in functionally and mechanistically defining immune activation after TBI. In this review, we explore the burgeoning evidence implicating the acute release of damage associated molecular patterns (DAMPs), such as adenosine 5'-triphosphate (ATP), high mobility group box protein 1 (HMGB1), S100 proteins, and hyaluronic acid in the initiation of progressive neurological injury, including white matter loss after TBI. The role that pattern recognition receptors, including toll-like receptor and purinergic receptors, play in progressive neurological injury after TBI is detailed. Finally, we provide support for the notion that resident and infiltrating macrophages are critical cellular targets linking acute DAMP release with adaptive immune responses and chronic injury after TBI. The therapeutic potential of targeting DAMPs and barriers to clinical translational, in the context of TBI patient management, are discussed.

Keywords: HMGB1; Leukocyte; Lymphocyte; Macrophage; Microglia; Oligodendrocyte; S100; T-cell; Toll like receptor; White matter injury.

FIGURE 1. Proposed mechanism of white matter injury after TBI

(1) Following TBI, the release of DAMPs from necrotic neurons activate and polarize microglia and infiltrating macrophages toward a pro-inflammatory M1 phenotype. Activated macrophages phagocytose dead/dying cells and myelin debris to initiate the process of neurological recovery. (2) Antigen loaded, M1 macrophages migrate to deep cervical lymph nodes to present antigen (e.g. myelin) to naïve T cells (T_H0) cells. (3) M1 macrophages, which predominate after TBI, drive pro-inflammatory T_H1/T_H17 polarization to provide long-lasting, antigen-specific immunity by direct MHC Class II dependent antigen presentation and/or via the release of phenotype specific cytokines. (4) The subsequent migration of T_H1/T_H17 cells into the CNS leads to maladaptive immune responses against white matter (e.g. neurons, oligodendrocytes (OL), oligodendrocyte progenitor cells (OPC)). White matter loss results in further tissue destruction, secondary DAMP release, and chronic perpetuation of a pro-inflammatory feedback loop that culminates in neurological dysfunction.