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Review

The NLRP1 Inflammasome in Human Skin and Beyond

1
Department of Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland
2
Faculty of Medicine, University of Zurich, 8091 Zurich, Switzerland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(13), 4788; https://doi.org/10.3390/ijms21134788
Received: 15 June 2020 / Revised: 2 July 2020 / Accepted: 3 July 2020 / Published: 6 July 2020
(This article belongs to the Special Issue Inflammasome)
Inflammasomes represent a group of protein complexes that contribute to host defense against pathogens and repair processes upon the induction of inflammation. However, aberrant and chronic inflammasome activation underlies the pathology of numerous common inflammatory diseases. Inflammasome assembly causes activation of the protease caspase-1 which in turn activates proinflammatory cytokines and induces a lytic type of cell death termed pyroptosis. Although NLRP1 (NACHT, leucine-rich repeat and pyrin domain containing 1) was the first inflammasome sensor, described almost 20 years ago, the molecular mechanisms underlying its activation and the resulting downstream events are incompletely understood. This is partially a consequence of the poor conservation of the NLRP1 pathway between human and mice. Moreover, recent evidence demonstrates a complex and multi-stage mechanism of NLRP1 inflammasome activation. In contrast to other inflammasome sensors, NLRP1 possesses protease activity required for proteolytic self-cleavage and activation mediated by the function-to-find domain (FIIND). CARD8 is a second FIIND protein and is expressed in humans but not in mice. In immune cells and AML (acute myeloid leukemia) cells, the anti-cancer drug talabostat induces CARD8 activation and causes caspase-1-dependent pyroptosis. In contrast, in human keratinocytes talabostat induces NLRP1 activation and massive proinflammatory cytokine activation. NLRP1 is regarded as the principal inflammasome sensor in human keratinocytes and UVB radiation induces its activation, which is believed to underlie the induction of sunburn. Moreover, gain-of-function mutations of NLRP1 cause inflammatory skin syndromes and a predisposition for the development of skin cancer. SNPs (single nucleotide polymorphisms) of NLRP1 are associated with several (auto)inflammatory diseases with a major skin phenotype, such as psoriasis or vitiligo. Here, we summarize knowledge about NLRP1 with emphasis on its role in human keratinocytes and skin. Due to its accessibility, pharmacological targeting of NLRP1 activation in epidermal keratinocytes represents a promising strategy for the treatment of the numerous patients suffering from NLRP1-dependent inflammatory skin conditions and cancer. View Full-Text
Keywords: NLRP1; CARD8; inflammasome; skin; keratinocyte; inflammation NLRP1; CARD8; inflammasome; skin; keratinocyte; inflammation
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MDPI and ACS Style

Fenini, G.; Karakaya, T.; Hennig, P.; Di Filippo, M.; Beer, H.-D. The NLRP1 Inflammasome in Human Skin and Beyond. Int. J. Mol. Sci. 2020, 21, 4788. https://doi.org/10.3390/ijms21134788

AMA Style

Fenini G, Karakaya T, Hennig P, Di Filippo M, Beer H-D. The NLRP1 Inflammasome in Human Skin and Beyond. International Journal of Molecular Sciences. 2020; 21(13):4788. https://doi.org/10.3390/ijms21134788

Chicago/Turabian Style

Fenini, Gabriele, Tugay Karakaya, Paulina Hennig, Michela Di Filippo, and Hans-Dietmar Beer. 2020. "The NLRP1 Inflammasome in Human Skin and Beyond" International Journal of Molecular Sciences 21, no. 13: 4788. https://doi.org/10.3390/ijms21134788

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