Inflammasome and toll-like receptor signaling in human monocytes after successful cardiopulmonary resuscitation

Abstract

BackgroundWhole body ischemia-reperfusion injury (IRI) after cardiopulmonary resuscitation (CPR) induces a generalized inflammatory response which contributes to the development of post-cardiac arrest syndrome (PCAS). Recently, pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and inflammasomes, have been shown to mediate the inflammatory response in IRI. In this study we investigated monocyte PRR signaling and function in PCAS.MethodsBlood samples were drawn in the first 12 hours, and at 24 and 48 hours following return of spontaneous circulation in 51 survivors after cardiac arrest. Monocyte mRNA levels of TLR2, TLR4, interleukin-1 receptor-associated kinase (IRAK)3, IRAK4, NLR family pyrin domain containing (NLRP)1, NLRP3, AIM2, PYCARD, CASP1, and IL1B were determined by real-time quantitative PCR. Ex vivo cytokine production in response to stimulation with TLR ligands Pam3CSK4 and lipopolysaccharide (LPS) was assessed in both whole blood and monocyte culture assays. Ex vivo cytokine production of peripheral blood mononuclear cells (PBMCs) from a healthy volunteer in response to stimulation with patients’ sera with or without LPS was assessed. The results were compared to 19 hemodynamically stable patients with coronary artery disease.ResultsMonocyte TLR2, TLR4, IRAK3, IRAK4, NLRP3, PYCARD and IL1B were initially upregulated in patients following cardiac arrest. The NLRP1 and AIM2 inflammasomes were downregulated in resuscitated patients. There was a significant positive correlation between TLR2, TLR4, IRAK3 and IRAK4 expression and the degree of ischemia as assessed by serum lactate levels and the time until return of spontaneous circulation. Nonsurvivors at 30 days had significantly lower mRNA levels of TLR2, IRAK3, IRAK4, NLRP3 and CASP1 in the late phase following cardiac arrest. We observed reduced proinflammatory cytokine release in response to both TLR2 and TLR4 activation in whole blood and monocyte culture assays in patients after CPR. Sera from resuscitated patients attenuated the inflammatory response in cultured PBMCs after co-stimulation with LPS.ConclusionsSuccessful resuscitation from cardiac arrest results in changes in monocyte pattern recognition receptor signaling pathways, which may contribute to the post-cardiac arrest syndrome.Trial registrationThe trial was registered in the German Clinical Trials Register (DRKS00009684) on 27/11/2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1340-3) contains supplementary material, which is available to authorized users.

Disseminated intravascular coagulation in cardiac arrest and resuscitation

“…High levels of IL‐1 and catecholamine were observed in patients after cardiac arrest and resuscitation . Furthermore, IL‐1 mRNA expression and its protein production by monocytes was confirmed in these patients . Extremely high levels of adrenaline, approximately 2700 times greater than the normal range, may occur because of exogenous administration of adrenaline during CPR .…”

“…Monocytes purified from the blood of patients after cardiac arrest and resuscitation showed upregulation of TLR2, TLR4, IRAK4, and NLRP3 mRNAs from the early period (~12 hours) to the late period (~48 hours) after emergency department (ED) admission . In the early period, the serum lactate level, which is a surrogate marker of ischemia, is positively correlated with monocyte expression of TLR2, TLR4, and IRAK4.…”

Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review

“…In other words, it may be hypothesized that some known or unknown factors may determine the main roles played by the inflammasomes during HCC. For example, participation, or not, of other innate immunity pathways such as TLRs, may be considered as the important reason for the involvement of the inflammasomes in the HCC protection or progression because of their roles in the production of priming signals [28,30]. Previous investigations showed that microRNA223 has anti-cancerous properties [86,87].…”

“…Additionally, ATP binding to the purinergic receptor P2 × 7 and activation of cathepsins result in activation of the inflammasomes [26][27][28][29]. There is some evidence which demonstrated that inflammasomes need priming signals to be activated by the ligands [28,30]. The priming signals are derived from other innate immunity receptors such as toll-like receptors (TLRs) [28,30].…”

“…There is some evidence which demonstrated that inflammasomes need priming signals to be activated by the ligands [28,30]. The priming signals are derived from other innate immunity receptors such as toll-like receptors (TLRs) [28,30]. The priming signals not only induce activation of the inflammasomes, but also increase expression of the molecules at both mRNA and protein levels [31,32].…”