Reduced NLRP3 Gene Expression Limits the IL-1β Cleavage via Inflammasome in Monocytes from Severely Injured Trauma Patients

Abstract

Objective Traumatic injury or severe surgery leads to a profound immune response with a diminished functionality of monocytes and subsequently their IL-1β release. IL-1β plays an important role in host immunity and protection against infections. Its biological activation via IL-1β-precursor processing requires the transcription of inflammasome components and their activation. Deregulated activity of NOD-like receptor inflammasomes (NLR) like NLRP3 that leads to the maturation of IL-1β has been described in various diseases. While the role of other inflammasomes has been studied in monocytes, nothing is known about NLRP3 inflammasome after a traumatic injury. Here, the role of the NLRP3 inflammasome in impaired monocyte functionality after a traumatic injury was analyzed. Measurements and Main Results Ex vivo-in vitro stimulation of isolated CD14+ monocytes with lipopolysaccharide (LPS) showed a significantly higher IL-1β secretion in healthy volunteers (HV) compared to trauma patients (TP) after admission. Reduced IL-1β secretion was paralleled by significantly lowered gene expression of NLRP3 in monocytes from TP compared to those of HV. Transfection of monocytes with NLRP3-encoding plasmid recovered the functionality of monocytes from TP regarding the IL-1β secretion. Conclusions This study demonstrates that CD14+ monocytes from TP are significantly diminished in their function and that the presence of NLRP3 components is necessary in recovering the ability of monocytes to produce active IL-1β. This recovery of the NLRP3 inflammasome in monocytes may imply a new target for treatment and therapy of immune suppression after severe injury.

Differences in monocyte subsets are associated with short‐term survival in patients with septic shock

“…Interestingly, sepsis and septic shock affect not only monocyte subsets frequency, but also their activation status represented by surface expression of CD86 and HLA‐DR 28,29 . We observed significantly decreased surface expression of CD86 on classical monocytes and non‐significant decrease trend in intermediate and non‐classical monocytes.…”

Acute Alcohol Intoxication Modulates Monocyte Subsets and Their Functions in a Time-Dependent Manner in Healthy Volunteers

“…Therefore, along with the endotoxin tolerance, excessively alcoholized subjects may be susceptible to the development of secondary infections. Ex vivo in vitro LPS stimulation of monocytes shows a downregulation of NLRP3 expression in samples obtained from severely injured patients compared to healthy subjects ( 53 ). This in turn elicits the synthesis and release of active IL-1β ( 53 ), whereby the monocyte deactivation correlates with the injury severity ( 54 ).…”

“…Ex vivo in vitro LPS stimulation of monocytes shows a downregulation of NLRP3 expression in samples obtained from severely injured patients compared to healthy subjects ( 53 ). This in turn elicits the synthesis and release of active IL-1β ( 53 ), whereby the monocyte deactivation correlates with the injury severity ( 54 ). In a rat model of blunt chest thorax trauma and hemorrhagic shock with subsequent resuscitation, monocytes express lower levels of caspase-1 in response to ethanol administration 2 hours before injury ( 21 ).…”

Rapid Inflammasome Activation Is Attenuated in Post-Myocardial Infarction Monocytes

“…Despite the essential role of inflammasome complexes in immune surveillance, increasing evidence suggests that inflammasome dysregulation drives the course of chronic inflammatory diseases ( 14 ). Nonetheless, inflammasome activation can also undergo suppression as observed in severe trauma ( 15 ). Such traumatic experiences can be also faced to various degrees by cardiac tissue areas upon an ischemic insult.…”