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Nlrp1 inflammasome is downregulated in trauma patients

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Abstract

After a major trauma, IL-1β-producing capacity of monocytes is reduced. Generation of IL-1β is important for appropriate immune response after trauma and requires not only synthesis and transcription of inflammasome components but also their activation. Altered IL-1β-processing due to deregulated NLRP inflammasomes assembly is associated with several inflammatory diseases. However, the precise role of NLRP1 inflammasome in monocytes after trauma is unknown. Here, we investigated if NLRP1 inflammasome components are responsible for depressed monocyte function after trauma. We found in ex vivo in vitro assays that LPS-stimulation of CD14+-isolated monocytes from healthy volunteers (HV) results in remarkably higher capacity of the IL-1β-release compared to trauma patients (TP). During the 10-day time course, this monocyte depression was highest immediately after admission. Inflammasome activation correlating with this inflammatory response was demonstrated by enhanced protein production of cleaved IL-1β and caspase-1. Furthermore, we found that the gene expression of IL-1β, caspase-1, and ASC was comparable in TP and HV after LPS-stimulation during the 10-day course, while NLRP1 was markedly reduced in TP. We demonstrated that transfected monocytes from TP, which expressed the lacking components, were recovered in their LPS-induced IL-1β-release and that lacking of NLRP1 is responsible for the suppressed monocyte activity after trauma. The restoration of NLRP1 inflammasome suggests new mechanistic target for the recovery of dysbalanced immune reaction after trauma.

Key message

  • Suppression in monocyte function occurs early after a major trauma or surgery.

  • Reduced gene expression abrogates NLRP1 inflammasome assembly after trauma.

  • Limited availability of inflammasome components may cause reduced host defense.

  • Restoring NLRP1 in immune-suppressed monocytes recovers NLPR1 activity after trauma.

  • Recovered inflammasome activity may improve the immune response to PAMPs/DAMPs.

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Abbreviations

AIS:

Abbreviated injury scale

ASC:

Apoptosis-associated speck-like protein containing CARD

BSA:

Bovine serum albumin

CARD:

Caspase activation and recruitment domain

CASP1:

Caspase-1

CD:

Cluster of differentiation

Ctrl:

Control

DAMP:

Damage-associated molecular pattern

ED:

Emergency department

ELISA:

Enzyme-linked immunosorbent assay

EDTA:

Ethylenediaminetetraacetic acid

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HV:

Healthy volunteers

ICU:

Intensive care unit

IL:

Interleukin

ISS:

Injury severity score

LRR:

Leucin-rich repeats

LPS:

Lipopolysaccharide

mRNA:

Messenger ribonucleic acid

NLR:

NOD-like receptor

Nlrp:

NLR sensor molecule containing pyrin domaine

PBS:

Phosphate-buffered saline

PAMPs:

Pathogen-associated molecular pattern

PC:

Plasmid ctrl

PRR:

Pattern recognition receptors

PYCARD:

Gene encoding for ASC

TP:

Trauma patients

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Acknowledgments

BR was supported by the Frankfurter Forschungsfoerderung of the Goethe University Frankfurt within the funding program Foerderung von Nachwuchs forschern. JPH was supported by the Frankfurter Forschungsfoerderung of the Goethe University Frankfurt within the funding program Promotionsfoerderung.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Trauma, Hand and Reconstructive Surgery, Goethe University, Frankfurt, Germany

    B. Relja, J. P. Horstmann, K. Kontradowitz, K. Jurida, A. Schaible & I. Marzi

  2. Trauma Department, Hannover Medical School, Hannover, Germany

    C. Neunaber

  3. Department of General and Visceral Surgery, Goethe University, Frankfurt, Germany

    E. Oppermann

Authors
  1. B. Relja
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  2. J. P. Horstmann
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  3. K. Kontradowitz
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  4. K. Jurida
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  5. A. Schaible
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  6. C. Neunaber
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  7. E. Oppermann
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  8. I. Marzi
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Corresponding author

Correspondence to B. Relja.

Additional information

Parts of this study have been published as meeting abstracts.

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Relja, B., Horstmann, J.P., Kontradowitz, K. et al. Nlrp1 inflammasome is downregulated in trauma patients. J Mol Med 93, 1391–1400 (2015). https://doi.org/10.1007/s00109-015-1320-0

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  • DOI: https://doi.org/10.1007/s00109-015-1320-0

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