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Inflammasome mRNA Expression in Human Monocytes during Early Septic Shock

¹ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine; ² The Dorothy M. Davis Heart and Lung Research Institute; ³ Nationwide Children's Research Institute; and ⁴ Department of Statistics, The Ohio State University Medical Center, Columbus, Ohio

Correspondence and requests for reprints should be addressed to Mark D. Wewers, M.D., Division of Pulmonary, Critical Care, and Sleep Medicine, 201L DHLRI, 473 West 12th Avenue, Columbus, OH 43210-1252. E-mail: wewers.2{at}osu.edu

Rationale: 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.

Objectives: 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- 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-B–related genes.

Measurements and Main 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.

Key Words: inflammasome • monocytes • septic shock • messenger RNA • NALP1

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Novel intracellular sensors and regulators of caspase-1 (termed NLRs) modulate innate host responses. These NLRs assemble in response to bacterial and other exogenous challenges and induce major adaptive responses. What This Study Adds to the Field This study in critically ill humans shows that major changes in caspase-1 regulatory molecules occur in severe septic shock and correlate with the severity of illness.