Inflammasome proteins as biomarkers of traumatic brain injury

Abstract

BackgroundThe inflammasome plays an important role in the inflammatory innate immune response after central nervous system (CNS) injury. Inhibition of the inflammasome after traumatic brain injury (TBI) results in improved outcomes by lowering the levels of caspase-1 and interleukin (IL)-1b. We have previously shown that inflammasome proteins are elevated in the cerebrospinal fluid (CSF) of patients with TBI and that higher levels of these proteins were consistent with poorer outcomes after TBI when compared to patients that presented these inflammasome proteins at lower levels.Methods and findingsHere we extend our work by analyzing serum from 21 TBI patients and CSF from 18 TBI patients compared to 120 serum samples and 30 CSF samples from no-TBI donor controls for the expression of caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin(IL)-1b and IL-18. Analysis was carried out using the Ella Simple Plex system (Protein Simple) to determine the sensitivity and specificity of inflammasome proteins as biomarkers of TBI. Receiver operator characteristic (ROC) curves, confidence intervals and likelihood ratios for each biomarker was determined. ROC curves, confidence intervals, sensitivity and specificity for each biomarker examined revealed that caspase-1 (0.93 area under the curve (AUC)) and ASC (0.90 AUC) in serum and ASC (1.0 AUC) and IL-18 (0.84 AUC) in CSF are promising biomarkers of TBI pathology. Importantly, higher protein levels (above 547.6 pg/ml) of ASC (0.91 AUC) were consistent with poorer outcomes after TBI as determined by the Glasgow Outcome Scale-Extended (GOSE).ConclusionThese findings indicate that inflammasome proteins are excellent diagnostic and predictive biomarkers of TBI.

Interleukin-1 Beta Neutralization Attenuates Traumatic Brain Injury-Induced Microglia Activation and Neuronal Changes in the Globus Pallidus

“…To date, TNF-α has been evaluated mainly in experimental TBI models; however, several TNF-α targeting drugs, including e.g., infliximab and others have been approved for clinical use in autoimmune inflammatory diseases and evaluation in clinical TBI may be expected in the near future. The inflammasome is a crucial contributor to the inflammatory response, and IL-18 and other inflammasome associated proteins are increased in serum, cerebrospinal fluid and extracellular fluid in response to experimental and human TBI [59][60][61]. Furthermore, treatment with the naturally occurring inhibitor IL-18-binding protein (IL-18BP) improved recovery following experimental TBI [62].…”

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

“…Given that activation of NLRP3 inflammasome has been implicated in chronic neurodegeneration (Heneka et al, 2018) and TBI pathophysiology in humans (Adamczak et al, 2012;Kerr et al, 2018) and rodents (Liu et al, 2013;Xu et al, 2018;Kuwar et al, 2019), and that NOX2 may be an important upstream regulator of NLRP3 inflammasome activation (Dostert et al, 2008), we also examined molecular and cellular markers of this pathway. Key genes involved in NLRP3 inflammasome activation and function were chronically upregulated after TBI and reduced by PLX treatmentincluding Il1r1 and Casp1.…”

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

“…Furthermore, circulating ASC levels were found to have moderate ability to predict the severity of multiple sclerosis. In the context of TBI, this same group found that both ASC and caspase-1 (but not IL-1β or IL-18) were significantly upregulated in the serum of severe-TBI patients within the first 48 h of injury, with both proteins having excellent utility for distinguishing between control and TBI patients [104]. Interestingly, CSF levels of IL-18 and ASC were also assessed, with both proteins found to be at upregulated and accurate indicators of TBI.…”

“…Recent developments of highly sensitive assays, such as the single molecule array (SIMOA®), have resulted in lower detection limits and the ability to accurately quantify IL-1β in the periphery [119,120]. Similarly, the detection of NLRP3-related molecules such as ASC has been made possible due to assays available on the Ella Simple Plex System (ProteinSimple) [103,104]. Nonetheless, investigations into the ultimate utility of these novel biomarkers are somewhat hampered by the low accessibility to these specific immunoassay platforms.…”