ATP - NLRP3 Inflammasome Inducer

Extracellular ATP is a key danger-associated molecular pattern (DAMP) that is able to acitvate the NLRP3 inflammasome. It triggers the opening of the non-selective cation channel of the purinergic P2X7 receptor, followed by the subsequent alteration of the intracellular K+ concentration [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. Amores-Iniesta J, et al., 2017. Extracellular ATP Activates the NLRP3 Inflammasome and Is an Early Danger Signal of Skin Allograft Rejection. Cell Rep.;21(12):3414-3426.
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 ATP: