Uric acid acts as a natural adjuvant by promoting Th17 cell differentiation via an inflammasome-dependent mechanism (176.28)

Abstract

Abstract Non-microbial molecules released from damaged cells act as natural adjuvants capable of promoting an efficient immune response mediated by innate cells, including macrophages and dendritic cells (DCs). Among these molecules, uric acid (UA) in its crystallized form has been found to trigger inflammation through the activation of NLRP3 inflammasome, which leads to secretion of the proinflammatory cytokines IL-1β and IL-18. UA modulation of innate immune responses has been extensively studied, but the impact of this damage-associated molecular pattern on adaptive responses remains largely undocumented. As one of the most ubiquitous sterile danger signals in mammals, and in view of the key role played by UA in alum adjuvanticity, we sought to determine how UA crystals shape adaptive immune responses. In the present study, we focused on adaptive CD4+ T cell polarization since adjuvants that are able to direct appropriately polarized responses will be key to the success of next-generation vaccination strategies. In the presence of NF-κB signaling delivered by muramyl dipeptide, UA crystals were capable of stimulating DCs to promote the release of cytokines associated with Th17 polarization. Accordingly, UA crystals potently induced Th17 responses both in vitro and in vivo. These effects were dependent on the inflammasome-related cytokines IL-1α/β and IL-18, as well as on ASC and caspase-1. Accordingly, NLRP3 deficiency significantly impaired Th17 polarization, at least in vitro.