Abstract
Exposure to nickel (Ni(2+)) can trigger allergic reactions in susceptible individuals, which is widely accepted as the major cause of allergic contact hypersensitivity (CHS) worldwide. Although Ni(2+)-induced proinflammatory responses clearly play a pivotal role in CHS, the underlying molecular mechanism has not been fully defined. Here we report that Ni(2+) 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, Ni(2+) 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 Ni(2+) and provided a mechanistic basis for optimizing the therapeutic intervention against Ni(2+)-induced allergy in patients.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis Regulatory Proteins
-
CARD Signaling Adaptor Proteins
-
Carrier Proteins / metabolism*
-
Caspase 1 / metabolism*
-
Cell Line, Tumor
-
Cytoskeletal Proteins / metabolism*
-
Dendritic Cells / drug effects*
-
Dendritic Cells / enzymology
-
Dendritic Cells / immunology
-
Dermatitis, Allergic Contact / enzymology
-
Dermatitis, Allergic Contact / etiology*
-
Dermatitis, Allergic Contact / immunology
-
Dose-Response Relationship, Drug
-
Humans
-
Immunity, Innate / drug effects
-
Inflammasomes / drug effects
-
Inflammasomes / immunology
-
Inflammasomes / metabolism
-
Interleukin-1beta / metabolism*
-
Lysosomes / drug effects
-
Lysosomes / enzymology
-
Lysosomes / immunology
-
Macrophages / drug effects
-
Macrophages / enzymology
-
Macrophages / immunology
-
Mice
-
Mitochondria / drug effects
-
Mitochondria / enzymology
-
Mitochondria / immunology
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Nickel / toxicity*
-
Reactive Oxygen Species / metabolism
-
Signal Transduction / drug effects
Substances
-
Apoptosis Regulatory Proteins
-
CARD Signaling Adaptor Proteins
-
Carrier Proteins
-
Cytoskeletal Proteins
-
IL1B protein, human
-
IL1B protein, mouse
-
Inflammasomes
-
Interleukin-1beta
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
NLRP3 protein, human
-
Nlrp3 protein, mouse
-
PYCARD protein, human
-
Pycard protein, mouse
-
Reactive Oxygen Species
-
nickel chloride
-
Nickel
-
Caspase 1