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.

Innate immune responses to trauma

“…When exposed to DAMPs, phagocytic microglia are rapidly activated to clear debris (for example, a hematoma), seal defective barriers and produce neurotrophic factors 105–107 . However, microglia are also critical for an extensive and often sustainable (up to years) generation of cytokines (for example, IL-1β and IL-6) and ROS, which in turn recruit neutrophils and blood monocytes-macrophages to the injured area 103,105,108 . Furthermore, complement 109 or lysophosphatidylcholine activates inflammasomes in microglia or astrocytes soon after TBI and during neuro-inflammation 110 .…”

“…The multifactor-driven development of edema, increased intracranial pressure and reduced cerebral perfusion pressure and blood flow constitute a vicious cycle that amplifies the hypoxic conditions that disrupt the energy supply (ATP) in the brain. These intracerebral changes often lead to additional damage to white and gray matter 105 and a sustained reduction in synaptic plasticity.…”

Cognition and Intervention in Traumatic Brain Injury

“…Cerebral damage in traumatic brain injury (TBI) may be accompanied by headache, of varying intensities and localizations, dizziness and illfeeling, loss of consciousness, blurring of vision, hearing impediments, confusion states, loss of memory and cognitive capacity, seizure activity, paralysis and coma as the primary-registered symptoms and expressions, with the expectation of accompanying damage to bloodbrain-barrier integrity, accelerated apoptosis and excitotoxicity [4][5][6]. Further, there is a profusion of balance and attentive disorders in TBI independent of several other injury parameters.…”

Immune and metabolic alterations following trauma and sepsis – An overview

“…In another article, Dhandapani and colleagues discuss the emerging concept on the possible role of damage associated molecular patterns (DAMPS) in white matter damage following TBI [13]. They provide an overview of recent reports to substantiate the argument that progressive neurological injury is mediated by DAMPS such as HMGB1 (high mobility group box protein 1) and ATP (adenosine triphosphate) after TBI.…”

“…Their article highlights the need to identify the relationship between immune response and white matter injury following TBI to develop more targeted treatment strategies for these patients. The article by Dhandapani group and the review by Efron and colleagues on the role of DAMPs and PAMPs in injury and infection highlight the significance and the current research trend on the role of these danger signals in trauma and sepsis [8,13]. …”