Neutrophils and the NLRP3 inflammasome: a tale of proteases, kinases, and inflammation

Neutrophils are key first responders to both infectious and noninfectious stress, playing a pivotal role in maintaining homeostasis through tightly regulated activation states and the release of inflammatory mediators. The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a key regulator of inflammation and has been extensively studied in monocytes and macrophages. However, recent research has shifted focus to the NLRP3 inflammasome in neutrophils and has highlighted its role in neutrophil activation and the production of inflammatory mediators. For example, neutrophils express a functional NLRP3 inflammasome with activation dynamics similar to those observed in monocytes. Canonical inflammasome activation is triggered by stimuli such as lipopolysaccharide and adenosine triphosphate via P2X7 receptor signaling, leading to interleukin-1β release. However, neutrophils also exhibit distinct characteristics, including the involvement of proteases other than caspase-1, differential regulation by kinases such as Bruton's tyrosine kinase, and the release of neutrophil extracellular traps and neutrophil proteases upon NLRP3. Moreover, apoptosis-associated speck-like protein containing a CARD (ASC)0-independent Nod-like receptor family pyrin domain containing 3 functions have been described. A picture emerges in which the interplay between NLRP3 activation and unique neutrophil functions is critical in various pathological contexts, yet the mechanisms and downstream effects remain underexplored. With a particular emphasis on the human system, this review aims to summarize current knowledge of NLRP3 inflammasome function in neutrophils. Given the essential need to consider the role of neutrophils in NLRP3-targeting approaches, it also seeks to highlight critical open questions that warrant further research.