Persistent NLRP3 inflammasome activation is associated with delayed immunosuppression in septic patients.

Sepsis triggers a complex response marked by the simultaneous presence of pro-inflammatory and immunosuppressive elements, disrupting the mechanisms intended to maintain homeostasis. While the NLRP3 inflammasome has been demonstrated to contribute to the inflammatory side, its connection with delayed sepsis-induced immunosuppression remains unexplored. The present objective was to concomitantly and prospectively assess NLRP3 activation (IL-1β, IL-18 and soluble receptors) and features of immune failure (IL-10, mHLA-DR, MDSC) in septic patients. To validate our findings, we conducted a transcriptomic analysis of mRNA of NLRP3 related genes (IL-18R1, IL-1R2) on an additional cohort of 107 patients. Two distinct endotypes of endotypes were identified. One cluster displayed moderate inflammation rapidly returning to normal values, while the other exhibited a higher inflammatory response persisting until day 28 which was associated with persistent marked immunosuppression and higher 28-day mortality. Identifying endotypes with different pro-/anti-inflammatory trajectories could hold important clinical implications for the management of sepsis.