Nickel Induces Interleukin-1β Secretion via the NLRP3–ASC–Caspase-1 Pathway

Exposure to nickel (Ni²⁺) can trigger allergic reactions in susceptible individuals, which is widely accepted as the major cause of allergic contact hypersensitivity (CHS) worldwide. Although Ni²⁺-induced proinflammatory responses clearly play a pivotal role in CHS, the underlying molecular mechanism has not been fully defined. Here we report that Ni²⁺ activates the NLRP3–ASC–caspase-1 immune signaling pathway in antigen-presenting cells, leading to the proteolytic processing and secretion of a proinflammatory cytokine, interleukin-1β (IL-1β). The activation of this signaling axis is independent of phagolysosome–cathepsin B pathway. Instead, Ni²⁺ induces mitochondrial reactive oxygen species accumulation and cation fluxes, both of which are required for activating the NLRP3–ASC–caspase-1 pathway. Together, these results identified a novel innate immune signaling pathway (NLRP3–ASC–caspase-1–IL-1β) activated by Ni²⁺ and provided a mechanistic basis for optimizing the therapeutic intervention against Ni²⁺-induced allergy in patients.