Human inflammasomes are novel sensors of lipids

Abstract

The innate immune system is the first line of host defense. Upon detecting pathogens or cell stress, some NOD-like receptors (NLRs) and absent in melanoma (AIM)-like receptors (ALRs) recruit the adaptor protein ASC and consecutively the protease pro-caspase-1, forming an intracellular complex called an inflammasome. Inflammasome formation induces pro-caspase-1 activation, which in turn triggers gasdermin D-dependent pyroptotic cell death and the subsequent release of the pro-inflammatory cytokines interleukin (IL)-1&beta; and IL-18. The exact triggers and activation mechanisms of several inflammasome-forming sensors remain a topic of active research. <br/> Recently, lipid-based mRNA vaccines have been shown to induce the production of IL-1&beta; in human peripheral blood mononuclear cells (PBMCs). Here we show that several human inflammasomes, such as NLRP3 and AIM2, can sense the lipid nanoparticle (LNP)-mRNA Pfizer and Moderna COVID-19 vaccines as well as the transfection reagent lipofectamine 2000, causing ASC speck formation and cytokine release. We speculate that the inflammasomes could sense the lipid nanoparticles and not the mRNA component of these vaccines. Interestingly, mouse inflammasomes do not seem to have the same sensitivity to these vaccines, as they do not activate inflammasomes upon vaccine treatment. <br/> Our findings might explain the inflammatory side effects of LNP-mRNA vaccines, such as fever and arm swelling, but also, potentially, the adjuvant mechanism of these novel vaccines. Better characterization of inflammasome-activating lipids could aid the development of improved LNP-based mRNA vaccines that elicit a fine-tuned inflammatory response. Finally, due to differences in inflammasome sensing of LNP-mRNA vaccines between humans and mice, we propose that wild-type mice may not be the best model to study immuno- and reactogenicity of newly developed mRNA vaccines.