The NLRP3 inflammasome plays a role in the inflammatory response to vaccines, in anti-microbial host defense, and in autoimmune diseases. However, its mechanism of action remains incompletely understood. NLRP3 has been shown to be activated by diverse stimuli including microbial toxins, ATP, particulate matter, etc. that can activate multiple cellular processes. The chemical complicity and structural diversity of known inflammasome activators has made it difficult to identify a minimum requirement for inflammasome activation. Here we show that rupture of the lysosome alone can serve as a regulator for inflammasome activation by employing a new, switchable polymeric lysosomal rupture probe. By controlling the structure of the polymers, we show that polymers with the same chemical composition in different proportions can differentially activate the inflammasome based solely on their degree of lysosomal escape. Specifically, polymers with poorer lysosomal escape have proportionally weaker inflammasome responses. These results provide new insight into the activity of the NLRP3 inflammasome confirming a minimal mechanistic requirement which will help guide therapeutic interventions that might prevent or mitigate lysosomal rupture as well as provide a predictive framework for dosable activation of the NLRP3 inflammasome for potential therapeutic applications in vaccines and immunotherapies.

Tunable polymeric lysosomal rupture probe to investigate mechanism of NLRP3 Inflammasome activation

255th National Meeting (2018)

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