Franklin L. Zhong1,2*, Ons Mamaï1,4*, Lorenzo Sborgi3, Lobna Boussofara5, Richard Hopkins2, Kim Robinson1,, Ildikó Szeverényi1, Takuya Takeichi6,13, Reshmaa Balaji1, Aristotle Lau1, Hazel Tye10,11, Keya Roy1,, Carine Bonnard1, Patricia J. Ahl2, Leigh Ann Jones2, Paul Baker10.11, Lukas Lacina1, Atsushi Otsuka7, Pierre R. Fournie8.9, François Malecaze8.9, E. Birgitte Lane1, Masashi Akiyama6, Kenji Kabashima1,7, John E. Connolly2, Seth L. Masters10,11, Vincent J. Soler8,9, Salma Samir Omar12, John A. McGrath13, Roxana Nedelcu14, Moez Gribaa4, Mohamed Denguezli5, Ali Saad4, Sebastian Hiller3, Bruno Reversade1,2,15,16,#
1 Institute of Medical Biology, A*STAR, Singapore
2 Institute of Molecular and Cellular Biology, A*STAR, Singapore
3 Biozentrum, University of Basel, 4056 Basel, Switzerland
4 Laboratory of Human Cytogenetic, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse, Tunisia
5 Department of Dermatology and Venerology, Farhat Hached University Hospital, Sousse, Tunisia
6 Department of Dermatology, Nagoya University Graduate School of Medicine, Japan
7 Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
8 Ophthalmology Department, Hôpital Pierre-Paul Riquet, University Toulouse Hospital, TSA 40031, Place Baylac 31059 Toulouse Cedex 9, France
9 Team « Epithéliums, physiopathologie et génétique oculaires », Unité "Différenciation Epithéliale et Autoimmunité Rhumatoïde"
UMR 1056 Inserm – Université Paul Sabatier Toulouse III, FRE 3742 CNRS, Hôpital Purpan, Toulouse, France
10 Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
11 Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
12 Department of Dermatology, Venereology & Andrology, Faculty of Medicine, Alexandria University, Egypt
13 St John's Institute of Dermatology, King's College London, Guy's Hospital, London, United Kingdom
14 Department of Pathophysiology II, National Institute for Infectious Diseases “Matei Bals”, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
15 Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey
16 Department of Paediatrics, National University of Singapore, Singapore
*These authors contributed equally to this work
Published in Cell. 2016 Sep 22;167(1):187-202.e17. doi: 10.1016/j.cell.2016.09.001.
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: Multiple Self-healing Palmoplantar Carcinoma (MSPC) and Familial Keratosis Lichenoides Chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function, and predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
Figure Legend: NLRP1 is a central regulator of skin immunity and inflammation. Figure demonstrates proposed mechanisms of NLRP1 inflammasome activation in skin keratinocytes in auto-inflammatory and skin cancer predisposition syndromes.
For more information on Bruno REVERSADE's lab, please click here.