1. ¹Departments of Dermatology and Pathology/Immunology, Geneva University Medical School, Geneva, Switzerland
2. ²Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
3. ³Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
4. ⁴Deptartment of Dermatology, Zurich University Hospital, Zürich, Switzerland

Correspondence: Professor Lars E. French, Department of Dermatology, Zurich University Hospital, Gloriastrasse 31, CH-8091 Zürich, Switzerland. E-mail: lars.french@usz.ch; Dr Olivier Gaide, Department of Dermatology and Pathology/Immunology, Geneva University Medical School, Michel-Servet 1, CH-1211 Geneva, Switzerland. E-mail: olivier.gaide@medecine.unige.ch

⁵These two authors contributed equally to this work.

⁶Current address: Harvard School of Public Health, Department of Immunology and Infectious Diseases, François-Xavier Bagnoud Bldg; Room FXB205, 651 Huntington Ave, Boston MA 02115, USA.

Received 30 October 2006; Revised 9 February 2007; Accepted 15 February 2007; Published online 12 April 2007.

Abstract

The inflammasome is a cytosolic protein complex regulating the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1 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-1/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-1 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.