Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity.
The inflammasome is a cytosolic protein complex regulating the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1beta and IL-18 into their active form. The inflammasome is composed of a NACHT-, LRR- and pyrin (NALP) family member that acts as a sensor for danger signals and the adaptor protein apoptosis-associated speck-like protein containing a CARD domain (ASC), which allows the recruitment of caspase-1 in the complex. In the skin, exposure to contact sensitizers (CS) such as trinitro-chlorobenzene causes an immune response called contact hypersensitivity (CHS) or eczema. In this delayed-type hypersensitivity response, efficient priming of the adaptive immunity depends on the concomitant activation of the innate immune system, including IL-1beta/IL-18 activation in the skin. To determine if the inflammasome contributes to CHS, we have analyzed its capacity to react to CS in vitro and in vivo. We show here that key components of the inflammasome are present in human keratinocytes and that CS like trinitro-chlorobenzene induce caspase-1/ASC dependent IL-1beta and IL-18 processing and secretion. We also show that ASC- and NALP3-deficient mice display an impaired response to CS. These findings suggest that CS act as danger signals that activate the inflammasome in the skin, and reveal a new role of NALP3 and ASC as regulators of innate immunity in CHS.
Watanabe
Hideki
H
Department of Dermatology, Geneva University Medical School, Geneva, Switzerland.
Gaide
Olivier
O
Pétrilli
Virginie
V
Martinon
Fabio
F
Contassot
Emmanuel
E
Roques
Stéphanie
S
Kummer
Jean A
JA
Tschopp
Jürg
J
French
Lars E
LE
D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000502:physiology; D003877:Dermatitis, Contact / Q000209:etiology*; D004139:Dinitrofluorobenzene / Q000633:toxicity; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology*; D020382:Interleukin-18 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010853:Picryl Chloride / Q000633:toxicity
D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D004139:Dinitrofluorobenzene; D020170:Caspase 1; D010853:Picryl Chloride