Inflammasome mRNA expression in human monocytes during early septic shock.
BACKGROUND
Monocytes are central to the initiation of the inflammatory response in sepsis, with caspase-1 activation playing a key role. Monocyte deactivation during sepsis has been linked to poor outcomes.


OBJECTIVE
Given the importance of caspase-1 in the immune response, we investigated whether monocytes from patients early in septic shock demonstrate alterations in mRNAs for caspase-1-related molecules.


METHODS
Patients with septic shock (n = 26; age >18 years), critically ill intensive care unit patients (n = 20), and healthy volunteers (n = 22) were enrolled in a prospective cohort study in a university intensive care unit. Demographic, biological, physiologic, and plasma cytokine measurements were obtained. Monocytes were assayed for ex vivo tumor necrosis factor-alpha production, and fresh monocyte mRNA was analyzed by quantitative reverse-transcription polymerase chain reaction for Toll-like receptors, NOD-LRR proteins, cytokines, and nuclear factor-kappaB-related genes.


RESULTS
Relative copy numbers for the inflammasome mRNAs for ASC, caspase-1, NALP1, and Pypaf-7 were significantly lower in patients with septic shock compared with critically ill control subjects. NALP1 mRNA levels were linked to survival in patients with sepsis (P = 0.0068) and correlated with SAPS II scores (r = -0.63).


CONCLUSIONS
These data suggest that monocyte deactivation occurs during the earliest stages of the systemic inflammatory response and that changes in inflammasome mRNA expression are part of this process.
Fahy
Ruairi J
RJ
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University Medical Center, Columbus, Ohio, USA.
Exline
Matthew C
MC
Gavrilin
Mikhail A
MA
Bhatt
Nitin Y
NY
Besecker
Beth Y
BY
Sarkar
Anasuya
A
Hollyfield
Jennifer L
JL
Duncan
Michelle D
MD
Nagaraja
Haikady N
HN
Knatz
Nina L
NL
Hall
Mark
M
Wewers
Mark D
MD
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics*; D016638:Critical Illness; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology; D000070576:NLR Proteins; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C476731:NLRP12 protein, human; C402202:PYCARD protein, human; D012333:RNA, Messenger; D020170:Caspase 1