CPPD Crystals - NLRP3 Inflammasome Inducer

Similar to uric acid, the causative agent of gout, CPPD crystals can act as endogenous danger signals that stimulate the innate immune system to produce inflammatory cytokines such as IL-1β. Engagement of the NRLP3 inflammasome is supported by the finding that macrophages from mice deficient in various components of the inflammasome did not respond to injection of CPPD crystals [1].

The NLRP3 inflammasome is an intracellular multi-protein complex that plays a central role in innate immunity. It is activated by a two-step process. A first signal (‘priming’) is provided by pathogen-associated molecular patterns (PAMPs) or cytokines. It allows the transcriptional upregulation of key inflammasome actors and the post-translational modification of NLRP3 . The second signal (‘activation’) is provided by a wide array of stimuli including microbial toxins, endogenous molecules or crystalline substances. The current paradigm is that NLRP3 does not bind directly to these molecules. Rather it senses downstream cytosolic stress signals such as K+ efflux. This  triggers inflammasome multimerization and pro-caspase-1 maturation. Proximity-induced autolytic activation of caspase-1 leads to the formation of gasdermin D (GSDMD) pores at the cell surface, allowing IL-1β/IL-18 and alarmin secretion, and ultimately, pyroptosis [3,4].

References:

1. Martinon F. et al., 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 440(7081):237-41
2. Swanson K.V. et al., 2019. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19:477.
3. Groslambert M. & Py B. 2018. Spotlight on the NLRP3 inflammasome pathway. J. Inflamm. Res. 11:359.

Chemical structure of CPPD Crystals: