Emerging Roles for the Immune System in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) affects an ever-growing population of all ages with long-term consequences on health and cognition. Many of the issues that TBI patients face are thought to be mediated by the immune system. Primary brain damage that occurs at the time of injury can be exacerbated and prolonged for months or even years by chronic inflammatory processes, which can ultimately lead to secondary cell death, neurodegeneration, and long-lasting neurological impairment. Researchers have turned to rodent models of TBI in order to understand how inflammatory cells and immunological signaling regulate the post-injury response and recovery mechanisms. In addition, the development of numerous methods to manipulate genes involved in inflammation has recently expanded the possibilities of investigating the immune response in TBI models. As results from these studies accumulate, scientists have started to link cells and signaling pathways to pro- and anti-inflammatory processes that may contribute beneficial or detrimental effects to the injured brain. Moreover, emerging data suggest that targeting aspects of the immune response may offer promising strategies to treat TBI. This review will cover insights gained from studies that approach TBI research from an immunological perspective and will summarize our current understanding of the involvement of specific immune cell types and cytokines in TBI pathogenesis.

Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

“…Traumatic brain injury (TBI) is the most common cause of injury-induced death and long-term disability worldwide, especially in children and young adults (1). Approximately 10 million people sustain new TBIs each year, with an estimated overall cost of ;U.S. $406 billion (2).…”

Innate immune responses to trauma

“…The initial insult often consists of meningeal and neuronal contusion, axonal shearing and damage to blood vessels in the meninx and the brain as the ‘primary TBI’. That acutely leads to glia limitans damage, meningeal cell death, neuronal damage and the activation of glial cells such as microglia and astrocytes, which release further DAMPs and produce an inflammatory response in brain 103,104 (Fig. 4).…”

“…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 .…”

“…After exposure to IL-1β, astrocytes rapidly generate immune signals in the form of extracellular vesicles dispatched to the periphery, which results in the further recruitment of neutrophils and systemic release of cytokines 111 . The resulting inflammatory response is associated with additional generation of ROS and release of excitatory neurotransmitters, further cellular recruitment of non-classical monocytes and neutrophils 112 and microcirculatory disturbances, which causes the progressive, often rapid transition to ‘secondary TBI’ 103 . Immigrated neutrophils help to clear debris such as myelin fragments but also aggravate inflammation and even neuronal loss.…”

The role of histone deacetylase inhibitors in regulation of Akt/GSK-3β signaling pathway in mice following transient focal cerebral ischemia

“…There are also many crosseffects among this different hypotheses, which makes the pathogenesis of ischemic stroke more complex 15 . In those hypotheses, oxidative stress and inflammatory response are the most classic, which mainly refers to that a large number of oxidized and inflammatory mediators released after cerebral ischemia reperfusion, leading directly to the functional impairment, affecting the proliferation and apoptosis of neurons, aggravating cerebral ischemia reperfusion injury 16,17 . Recent studies have shown that the gene expression in ischemic stroke is abnormal, whereas HDACI can regulate the expression of genes related to neurological function through acetylation/deacetylation by histone and nonhistone, reducing the injury, promoting the revascularization of ischemic area and promoting the neuronal plasticity and functional recovery 18,19 .…”