Monitoring the Neuroinflammatory Response Following Acute Brain Injury

Abstract

Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are major contributors to morbidity and mortality. Following the initial insult, patients may deteriorate due to secondary brain damage. The underlying molecular and cellular cascades incorporate components of the innate immune system. There are different approaches to assess and monitor cerebral inflammation in the neuro intensive care unit. The aim of this narrative review is to describe techniques to monitor inflammatory activity in patients with TBI and SAH in the acute setting. The analysis of pro- and anti-inflammatory cytokines in compartments of the central nervous system (CNS), including the cerebrospinal fluid and the extracellular fluid, represent the most common approaches to monitor surrogate markers of cerebral inflammatory activity. Each of these compartments has a distinct biology that reflects local processes and the cross-talk between systemic and CNS inflammation. Cytokines have been correlated to outcomes as well as ongoing, secondary injury progression. Alongside the dynamic, focal assay of humoral mediators, imaging, through positron emission tomography, can provide a global in vivo measurement of inflammatory cell activity, which reveals long-lasting processes following the initial injury. Compared to the innate immune system activated acutely after brain injury, the adaptive immune system is likely to play a greater role in the chronic phase as evidenced by T-cell-mediated autoreactivity toward brain-specific proteins. The most difficult aspect of assessing neuroinflammation is to determine whether the processes monitored are harmful or beneficial to the brain as accumulating data indicate a dual role for these inflammatory cascades following injury. In summary, the inflammatory component of the complex injury cascade following brain injury may be monitored using different modalities. Using a multimodal monitoring approach can potentially aid in the development of therapeutics targeting different aspects of the inflammatory cascade and improve the outcome following TBI and SAH.

Keywords: multimodal monitoring; neuroinflammation; secondary brain injury; subarachnoid hemorrhage; traumatic brain injury.

Figure 1

Conceptual summary of the neuroinflammatory response in acute brain injury. This illustration depicts some of the cellular and molecular sequelae and inflammatory cascades that occur following injury to the brain over time, divided into different compartments [cerebrospinal fluid (CSF), brain parenchyma, and vascular]. Initially, danger-associated molecular patterns (DAMPs) including double-stranded (ds)DNA, RNA, and brain-enriched proteins such as S100B provide early triggers to resident cells reflecting tissue injury and linking the initial insult to subsequent humoral and cellular cascades. These in turn lead to an increasingly cytotoxic environment promoting cellular responses, stimulating both immunocompetent cells in the central nervous system (resident microglia and astrocytes), as well as recruiting peripheral monocytes, through pattern recognition receptors (PRR) such as toll-like receptors (TLR). The secretion of cytokines, chemokines, and other potent chemotactic substances (including complement proteins) induces the recruitment of neutrophils and monocytes into the brain parenchyma through the increasingly permeable blood–brain barrier (BBB), as well as having a direct cytotoxic effect. Ongoing release of cytokines initiates a long-term inflammatory process, which allows the dynamic shift of macrophages and microglial canonical phenotype between M1 (classical activation) and M2 (alternative active presumably the result of antigen-presenting cells migrating from the periphery). These processes result in chronic inflammation as well as auto-immunization toward brain-enriched antigens. Key cytokines are highlighted in red. MBL, mannose-binding lectin; MASP, mannose-associated serine protease; MMP-9, matrix metalloproteinase 9.

Figure 2

Overlapping characteristics of the pathophysiology in subarachnoid hemorrhage (SAH). Simplified Venn diagram of the different pathophysiological processes that follow SAH. Rather than a linear relationship between vascular spasm, ischemia, and clinical deficit, these may be overlapping and also occur as distinct phenomena. Vascular spasm is most closely linked with endothelin-1-mediated vasoconstriction but may also encompass swelling of the vascular endothelium leading to an angiographic appearance of reduced contrast flow. Ischemia may result from an absolute reduction in blood flow, which may be complicated by local microvascular collapse or thrombosis, or even hyperemia causing localized swelling and reducing the capillary perfusion in that locality. Neurological deficits may be caused by frank ischemia and also result from phenomena such as cortical spreading depression.