title: Nlrp1 inflammasome is downregulated in trauma patients.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Goethe University, Frankfurt, Germany. info@bornarelja.com.
authors.forename: B
authors.initials: B
authors.lastname: Relja
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Goethe University, Frankfurt, Germany.
authors.forename: J P
authors.initials: JP
authors.lastname: Horstmann
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Goethe University, Frankfurt, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kontradowitz
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Goethe University, Frankfurt, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Jurida
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Goethe University, Frankfurt, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schaible
authors.affiliation: Trauma Department, Hannover Medical School, Hannover, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Neunaber
authors.affiliation: Department of General and Visceral Surgery, Goethe University, Frankfurt, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Oppermann
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Goethe University, Frankfurt, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Marzi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D016207:Cytokines; D005260:Female; D015870:Gene Expression; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D000070576:NLR Proteins; D012720:Severity of Illness Index; D014947:Wounds and Injuries / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D058847:Inflammasomes; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D000070576:NLR Proteins; C427903:NLRP1 protein, human
keywords: Immune suppression; Inflammasome; Monocytes; Nlrp