Redox control of the NLRP1 inflammasome

PROJECT SUMMARY
Inflammasomes detect intracellular danger-associated signals and trigger an inflammatory form of cell death
called pyroptosis. The danger signals that the related NLRP1 and CARD8 inflammasomes sense are unknown
and represent a major knowledge gap. Interestingly, small-molecule inhibitors of the serine proteases DPP8
and DPP9 (DPP8/9) were recently discovered to induce a danger signal that activates the NLRP1 and CARD8
inflammasomes. However, DPP8/9 inhibitors, in contrast to other inflammasome activators, induce pyroptosis
in only a fraction of sensitive cells over relatively long time periods. Thus, it is possible that the co-occurrence
of a second danger signal with DPP8/9 inhibition is required for full and rapid NLRP1 and CARD8 activation.
The central hypothesis of this application is that a lack of reactive oxygen species, or reductive stress, is the
second danger signal required to fully activate these inflammasomes. This hypothesis has been formulated on
the basis of preliminary data produced in the applicant’s laboratory and described in the application. The long-
term goal of this project is to understand why reductive stress is a danger signal that is closely monitored by
the innate immune system. The immediate objective of this application is to determine the molecular
mechanism by which reductive stress activates the NLRP1 and CARD8 inflammasomes. This project consists
of three specific aims: 1) to characterize the impact of oxidants and antioxidants on NLRP1 and CARD8
activation; 2) to determine the mechanism of GPX1-mediated NLRP1 and CARD8 inactivation; and 3) to
determine how TRX1 modulates NLRP1 activation. Successful completion of this project will fill a critical
knowledge gap by showing that reductive stress is a key danger signal that activates the NLRP1 and CARD8
inflammasomes. Overall, this work holds tremendous promise to reveal a fundamental new connection
between metabolic stress and innate immunity, and to eventually enable these complex inflammasomes to be
harnessed for therapeutic benefit.

Grant Number: 5R01AI163170-05
NIH Institute/Center: NIH
Principal Investigator: Daniel Bachovchin