Cerebrospinal Fluid NLRP3 is Increased After Severe Traumatic Brain Injury in Infants and Children

Abstract

Background Inflammasome-mediated neuroinflammation may cause secondary injury following traumatic brain injury (TBI) in children. The pattern recognition receptors NLRP1 and NLRP3 are essential components of their respective inflammasome complexes. We sought to investigate whether NLRP1 and/or NLRP3 abundance is altered in children with severe TBI. Methods Cerebrospinal fluid (CSF) from children (n=34) with severe TBI (Glasgow coma scale score [GCS] ≤8) who had externalized ventricular drains placed for routine care was evaluated for NLRP1 and NLRP3 at 0–24h, 25–48h, 49–72h, and >72h post-TBI and was compared to infection-free controls that underwent lumbar puncture to rule out CNS infection (n=8). Patient age, sex, initial GCS, mechanism of injury, treatment with therapeutic hypothermia, and 6 month Glasgow outcome score (GOS) were collected. Results CSF NLRP1 was undetectable in controls and detected in 2 TBI patients and at only <24h post-TBI. CSF NLRP3 levels were increased in TBI patients compared with controls at all time points, p<0.001. TBI patients ≤ 4 years of age had higher peak NLRP3 levels vs. patients > 4 (15.50 [3.65–25.71] vs. 3.04 [1.52–8.87] ng/mL, respectively; p=0.048). Controlling for initial GCS in multivariate analysis, peak NLRP3 > 6.63ng/mL was independently associated with poor outcome at 6 months. Conclusions In the first report of NLRP1 and NLRP3 in childhood neurotrauma we found that CSF NLRP3 is elevated in children with severe TBI and independently associated with younger age and poor outcome. Future studies correlating NLRP3 with other markers of inflammation and response to therapy are warranted.

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

“…One study performed by Lin et al found an upregulation of NLRP3, caspase-1, IL-1β, and IL-18 protein in the surgically resected cortex of severe-TBI patients in comparison with that of epilepsy patients [71]. Another recent clinical study analyzed cerebrospinal fluid (CSF) from severe-TBI pediatric patients at four time points post-injury, ranging from < 24 h to > 72 h [72], finding that pediatric TBI patients had higher CSF levels of NLRP3 than their age-matched controls (i.e., patients without TBI who underwent a lumbar puncture to rule out CNS infection). Furthermore, a CSF NLRP3 concentration > 6.63 ng/ml at any time point was associated with poorer neurological outcome as determined by the Glasgow Outcome Scale at 6 months post-TBI.…”

MCC950, the Selective Inhibitor of Nucleotide Oligomerization Domain-Like Receptor Protein-3 Inflammasome, Protects Mice against Traumatic Brain Injury

“…15,16 Such an implication might approach high significance when NLRP3 has been proposed as a biomarker in cerebrospinal fluid in TBI patients with poor prognosis. 17 Despite all these emerging backgrounds, little has been examined in application of NLRP3 inhibitors in TBI. Applying general neuroprotectives like omega-3 fatty acids or telmisartan in experimental TBI, there are some earlier studies to suggest the association with NLRP3 inhibition may account for the therapeutic effects.…”

A Mouse Model for Juvenile, Lateral Fluid Percussion Brain Injury Reveals Sex-Dependent Differences in Neuroinflammation and Functional Recovery

“…15 In children, the potential for a dysregulated immune response after TBI to the immature brain has been reported, and as such, evaluation of the brain cytokine response after juvenile FPI was warranted. [25][26][27] After lateral FPI in juvenile mice, we discovered rapid elevation in proinflammatory cytokines near the injury epicenter (cortex and underlying hippocampus) as well as in areas remote from impact (brainstem; Fig. 6).…”