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

Detecting and responding to noxious molecules internalized within the endolysosomal system, including bacterial toxins and particulate matter, is essential to prevent cellular intoxication and damage. Here, we demonstrate that the NLRP3 inflammasome detects perturbations of the endolysosomal system by large clostridial toxins, including toxin B from Clostridioides difficile , as well as monosodium urate and silica crystals in human macrophages. These molecules cause sodium efflux from the endolysosomal system into the cytosol, driving cytosolic sodium accumulation. The rapid increase in cytosolic sodium subsequently triggers cell swelling and inhibits endocytic trafficking to activate the NLRP3 inflammasome. Furthermore, we demonstrate that cytosolic sodium accumulation is a common trigger for NLRP3 activation by non-particulate stimuli, including nigericin and inhibition of the Na ⁺ /K ⁺ ATPase. Our findings reveal that accumulation of cytosolic sodium is the common denominator underlying activation of the NLRP3 inflammasome upon exposure to different danger signals.