Cell Volume Regulation Modulates NLRP3 Inflammasome Activation

Cell volume regulation is a primitive response to alterations in environmental osmolarity. The NLRP3 inflammasome is a multiprotein complex that senses pathogen- and danger-associated signals. Here, we report that, from fish to mammals, the basic mechanisms of cell swelling and regulatory volume decrease (RVD) are sensed via the NLRP3 inflammasome. We found that a decrease in extracellular osmolarity induced a K+-dependent conformational change of the preassembled NLRP3-inactive inflammasome during cell swelling, followed by activation of the NLRP3 inflammasome and caspase-1, which was controlled by transient receptor potential channels during RVD. Both mechanisms were necessary for interleukin-1β processing. Increased extracellular osmolarity prevented caspase-1 activation by different known NLRP3 activators. Collectively, our data identify cell volume regulation as a basic conserved homeostatic mechanism associated with the formation of the NLRP3 inflammasome and reveal a mechanism for NLRP3 inflammasome activation. [Display omitted] ► Cell swelling is a conserved danger signal for activation of the NLRP3 inflammasome ► NLRP3 proteins are in preassembled inactive complexes before stimulation ► Activation of the NLRP3 inflammasome depends on K+ efflux and TRP channel stimulation ► Hypertonic solutions prevent caspase-1 activation in an in vivo epileptic model