Cerebrospinal Fluid NLRP3 is Increased After Severe Traumatic Brain Injury in Infants and Children.
BACKGROUND
Inflammasome-mediated neuroinflammation may cause secondary injury following traumatic brain injury (TBI) in children. The pattern recognition receptors NACHT domain-, Leucine-rich repeat-, and PYD-containing Protein 1 (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 (EVD) placed for routine care was evaluated for NLRP1 and NLRP3 at 0-24, 25-48, 49-72, and >72 h 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 were collected.


RESULTS
CSF NLRP1 was undetectable in controls and detected in 2 TBI patients at only <24 h 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 versus 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 >6.63 ng/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.
Department of Critical Care Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.|Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jessica S
JS
Wallisch
Department of Critical Care Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA. dennis.simon2@chp.edu.|Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. dennis.simon2@chp.edu.|Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. dennis.simon2@chp.edu.
Dennis W
http://orcid.org/0000-0002-3824-2326
DW
Simon
Department of Critical Care Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.|Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Hülya
H
Bayır
Department of Critical Care Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.|Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Neurological Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Michael J
MJ
Bell
Department of Critical Care Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.|Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Patrick M
PM
Kochanek
Department of Critical Care Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.|Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Robert S B
RSB
Clark
D048868:Adaptor Proteins, Signal Transducing / Q000134:cerebrospinal fluid*; D000293:Adolescent; D051017:Apoptosis Regulatory Proteins / Q000134:cerebrospinal fluid*; D015415:Biomarkers; D000070642:Brain Injuries, Traumatic / Q000134:cerebrospinal fluid*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000134:cerebrospinal fluid*; D000070576:NLR Proteins
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C453881:NLRP3 protein, human
Biomarker; Inflammasome; NLRP1; NLRP3; Neuroinflammation; Pediatric; Secondary brain injury; Traumatic brain injury