Cell volume regulation modulates NLRP3 inflammasome activation

Abstract

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 the basic mechanisms of cell swelling and regulatory volume decrease (RVD) are sensed from fish to mammals by the NLRP3 inflammasome. We found that a decrease in extracellular osmolarity induced (i) a K+-dependent conformational change of the preassembled NLRP3-inactive inflammasome during cell swelling, followed by (ii) activation of the NLRP3 inflammasome and caspase-1, which was controlled by Transient Receptor Potential (TRP) channels during RVD. Both mechanisms were necessary for interleukin-1b processing. Increased extracellular osmolarity prevented caspase-1 activation by different known NLRP3 activators. Collectively, our data place cell volume regulation as a basic conserved homeostatic mechanism associated with the formation of the NLRP3 inflammasome and provides a mechanism for NLRP3 inflammasome activation.