The role of Annexin A1 in the modulation of the NLRP3 inflammasome

Annexins are well-known Ca(2+) phospholipid-binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti-inflammatory and pro-resolving properties through its binding to the FPR2/ALX Receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for IL-1beta release in response to activators of the NLRP3 inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL-1beta release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL-1beta, NLRP3 and caspase-1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co-localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti-inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2-independent manner.