The NLRP3 inflammasome in physiological and dysfunctional host response in human sepsis and critical illness: a narrative review.

BACKGROUND

The NLRP3 inflammasome is a cytosolic multiprotein complex that serves as a key regulator of innate immunity by reacting to pathogen- and damage-associated signals and orchestrating downstream inflammatory responses. Inflammasome activation induces caspase-1-dependent maturation of interleukin (IL)-1β, IL-18 and gasdermin D, which results in pyroptotic cell death.

MAIN TEXT: While tightly controlled inflammasome activation is essential for effective host defence and pathogen clearance, accumulating evidence implicates its dysregulation as a central driver of host response imbalance in critical illness. In conditions such as sepsis and acute respiratory distress syndrome, excessive activation contributes to hyperinflammation, endothelial dysfunction, immunothrombosis, and multi-organ failure. Conversely, insufficient or exhausted inflammasome responses may impair microbial clearance and predispose to secondary infections. These observations underscore the context-dependent and temporally dynamic role of inflammasome signalling as being either protective or pathogenic. Emerging therapeutic strategies aim to restore immune homeostasis through targeted modulation of inflammasome pathways, including IL-1 blockade (e.g., anakinra) and inhibition of upstream signalling components. However, clinical translation remains challenging, requiring improved patient stratification, biomarker-guided approaches, and a deeper understanding of disease heterogeneity.

CONCLUSIONS

Inflammasome signalling plays a highly dynamic role in critical illness, contributing to effective host defence, if functional, or to pathological inflammation, if dysregulated. Although targeted modulation of inflammasome pathways represents a promising therapeutic strategy, further research is needed to refine patient selection, identify reliable biomarkers, and better characterise disease heterogeneity to enable successful clinical translation.