Alum - NLRP3 Inflammasome Inducer

Aluminum salts (also referred to as alum), such as aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, are commonly used vaccine adjuvants, although their mode of action in vivo remains unclear [1]. Alum has been shown to trigger NLRP3 activation through lysosomal destabilization [2].  Interestingly, in vivo studies indicate a minimal role for the NLRP3 inflammasome in alum’s adjuvanticity [3]. The reason for this divergence between the in vitro and in vivo action of alum needs to be further investigated.

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 [4,5].

References:

1. Li H. et al., 2008. Cutting Edge: Inflammasome activation by Alum and Alum’s adjuvant effect are mediated by NLRP3. J Immunol. 181:17-21.
2. Hornung V. et al., 2008. Silica crystals and aluminium salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9:847-856.
3. Wen Y. & Shi Y., 2016. Alum: an old dog with new tricks. Emerg Microbes Infect.5:e25.
4. Swanson K.V. et al., 2019. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19:477.
5. Groslambert M. & Py B. 2018. Spotlight on the NLRP3 inflammasome pathway. J. Inflamm. Res. 11:359.