Cytosolic sodium accumulation is a common danger signal triggering NLRP3 inflammasome activation

Here, we identify acute cytosolic sodium accumulation as a key trigger for NLRP3 inflammasome activation. Large clostridial toxins, as well as monosodium urate and silica crystals, rapidly elevate cytosolic sodium by promoting its release from the endo/lysosomal system, triggering concurrent potassium efflux and extracellular sodium influx.

This rise in cytosolic sodium disrupts endocytic trafficking by collapsing the sodium gradient across endosomal membranes, leading to peripheral redistribution and activation of NLRP3. Importantly, non-particulate stimuli, including nigericin, also activate NLRP3 by this sodium-dependent mechanism. These findings position cytosolic sodium as a key downstream effector of potassium efflux and a central signal for NLRP3 activation across diverse stimuli.