Neuroimmune responses in the developing brain following traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of both acute and long-term morbidity in the pediatric population, leading to a substantial, long-term socioeconomic burden. Despite the increase in the amount of pre-clinical and clinical research, treatment options for TBI rely heavily on supportive care with very limited targeted interventions that improve the acute and chronic sequelae of TBI. Other than injury prevention, not much can be done to limit the primary injury, which consists of tissue damage and cellular destruction. Secondary injury is the result of the ongoing complex inflammatory pathways that further exacerbate tissue damage, resulting in the devastating chronic outcomes of TBI. On the other hand, some level of inflammation is essential for neuronal regeneration and tissue repair. In this review article we discuss the various stages of the neuroimmune response in the immature, pediatric brain in the context of normal maturation and development of the immune system. The developing brain has unique features that distinguish it from the adult brain, and the immune system plays an integral role in CNS development. Those features could potentially make the developing brain more susceptible to worse outcomes, both acutely and in the long-term. The neuroinflammatory reaction which is triggered by TBI can be described as a highly intricate interaction between the cells of the innate and the adaptive immune systems. The innate immune system is triggered by non-specific danger signals that are released from damaged cells and tissues, which in turn leads to neutrophil infiltration, activation of microglia and astrocytes, complement release, as well as histamine release by mast cells. The adaptive immune response is subsequently activated leading to the more chronic effects of neuroinflammation. We will also discuss current attempts at modulating the TBI-induced neuroinflammatory response. A better understanding of the role of the immune system in normal brain development and how immune function changes with age is crucial for designing therapies to appropriately target the immune responses following TBI in order to enhance repair and plasticity.