Background/Purpose: In response to infections and tissue damage NLRP3 and ASC-containing inflammasome protein complexes are assembled, which promote caspase-1 activation, IL-1b and IL-18 processing and release and pyroptosis. Caspase-1 is also responsible for the release of ASC danger particles, which perpetuate and propagate inflammasome responses to bystander cells. However, excessive or persistent activation causes inflammatory diseases, including Cryopyrin Associated Periodic Syndrome (CAPS). Hence, a well-balanced inflammasome response is crucial to maintain homeostasis. Therefore inflammasome regulatory proteins likely exist to maintain an appropriate level of activity and in particular, to limit its activity during the resolution phase of this response. We propose that PYD-only protein POP1 is one of these proteins.

Methods: Available datasets of CAPS patients in the NCBI Gene Expression Omnibus database were analysed for POP1 expression.   Monocyte/macrophage-expressing POP1 transgenic (TG) mice were generated and crossed with conditional NLRP3^A350V and Lysozyme M-Cre recombinase (CreL)-expressing mice. Offspring were analysed for CAPS by measuring body weight, survival and histological analysis. ASC-GFP particles were sorted by flow cytometry and used to trigger secondary inflammasome responses, which were analyzed in vitro and in vivo. Cytokines were analyzed by ELISA.

Results: Here we show that the PYD-only protein POP1 inhibits ASC-dependent inflammasome assembly by preventing inflammasome nucleation, and consequently interferes with caspase-1 activation, IL-1b and IL-18 release, pyroptosis and the release of ASC danger particles. Mice lack POP1, but transgenic POP1 expression in monocytes and macrophages protects mice from systemic inflammation triggered by ASC danger particles and CAPS-linked NLRP3mutations. CAPS patients exhibit reduced POP1 expression, suggesting that impaired POP1 expression may contribute to excessive inflammasome-driven inflammation. We further show that POP1 expression itself is regulated by IL-1b and propose that POP1 provides a regulatory feedback loop that shuts down excessive inflammatory responses and thereby prevents systemic inflammation.

Conclusion: POP1 provides a unique mechanism evolved in humans to enable more control for the essential inflammasome-mediated host defense system, thereby guarding against excessive and out of control responses that can cause inflammatory disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-pyrin-domain-only-protein-pop1-inhibits-nlrp3-dependent-inflammatory-disease/