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

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Abstract

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.

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Acknowledgements

NINDS Grants R01 NS38620 (RC) and U01 NS081041 (MB); NICHD T32 HD40686 (DS, JW).

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    Authors and Affiliations

    1. 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

      Jessica S. Wallisch, Dennis W. Simon, Hülya Bayır, Michael J. Bell, Patrick M. Kochanek & Robert S. B. Clark

    2. Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

      Jessica S. Wallisch, Dennis W. Simon, Hülya Bayır, Michael J. Bell, Patrick M. Kochanek & Robert S. B. Clark

    3. Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

      Jessica S. Wallisch, Dennis W. Simon, Hülya Bayır, Michael J. Bell, Patrick M. Kochanek & Robert S. B. Clark

    4. Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

      Hülya Bayır

    5. Department of Neurological Surgery, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

      Michael J. Bell

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    Correspondence to Dennis W. Simon.

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    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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    Jessica S. Wallisch and Dennis W. Simon have contributed equally to this work.

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    Wallisch, J.S., Simon, D.W., Bayır, H. et al. Cerebrospinal Fluid NLRP3 is Increased After Severe Traumatic Brain Injury in Infants and Children. Neurocrit Care 27, 44–50 (2017). https://doi.org/10.1007/s12028-017-0378-7

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