Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not

Abstract

Traumatic brain injury (TBI) is associated with high mortality and disability, with a substantial socioeconomic burden. With the standardization of the treatment process, there is increasing interest in the role that the secondary insult of TBI plays in outcome heterogeneity. The secondary insult is neither detrimental nor beneficial in an absolute sense, among which the inflammatory response was a complex cascade of events and can thus be regarded as a double-edged sword. Therefore, clinicians should take the generation and balance of neuroinflammation following TBI seriously. In this review, we summarize the current human and animal model studies of neuroinflammation and provide a better understanding of the inflammatory response in the different stages of TBI. In particular, advances in neuroinflammation using proteomic and transcriptomic techniques have enabled us to identify a functional specific delineation of the immune cell in TBI patients. Based on recent advances in our understanding of immune cell activation, we present the difference between diffuse axonal injury and focal brain injury. In addition, we give a figurative profiling of the general paradigm in the pre- and post-injury inflammatory settings employing a bow-tie framework.

Keywords: advance; bow-tie framework; neuroinflammation; take seriously; traumatic brain injury.

Figure 1

The crosstalk of cells in the neuroinflammation. After TBI, the microglia can interact with astrocytes, the oligodendrocyte, neurons, and NG2 cells through several pathways, and the “closed-loop” mechanisms of their communications remain unclear. In addition, the differentiation between the NG2 cells and polydendrocytes or oligodendrocytes is still not clear, and their difference might play a role in neuroinflammation. (black color: settled cell–cell crosstalk mechanisms, red color: possible crosstalk mechanisms need to be certified).

Figure 2

A brief comparison of the neuroinflammation in two main subtypes of TBI. In the FBI (the left side), it begins with the complement activation and the initiators (including HMGB1, HSP, and ATP) releasing from the damaged meninges and parenchyma within minutes following brain injury. Those compliments will bind to DAMP sensors such as purinergic receptors and TLRs that immediately induce resident microglia activation followed by inflammasome assembling. Then, a variable number of cytokines and chemokines generating and the NF-κB translocating into the nuclei induce an immunological reprogramming. Meanwhile, it can also induce the recruitment of neutrophils and macrophages to the injured meninges and/or perivascular regions, by which more chemokines and cytokines proliferate and the inflammatory response amplifies. In the DAI (the right side), in addition to the above-mentioned processes, the MBP is released from the damaged neural myelin involved in CSF circulation. T cells can be recruited to the damage site via a damaged BBB and/or meningeal lymphatic vessel, and the local APCs subsequently present it. Moreover, massively activated astrocytes and oligodendrocytes and their crosstalk can participate in immunogenic signal activation, which takes precedence over peripheral immune infiltration (such as neutrophils and macrophages).

Figure 3

Schematic representation of the time-related paradigm shift in neuroinflammation following TBI employing a bow-tie paradigm. The characteristic of immunogenicity in the CNS was high variability and fewer constraints pre-TBI. Then, in the core, the neuroinflammation is “compressed” by relatively regular rules or steps and processed into chronic neuroinflammation following TBI. Notably, there was a dynamic course of the functional diversity; temporal intensity of response; and dynamic changes in inflammatory gene expression, cell activation, and their interaction network.