The NLRP1 Inflammasome in Human Skin and Beyond

Abstract

<jats:p>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.</jats:p>

Pyroptosis: mechanisms and diseases

“… 162 , 416 – 418 Surprisingly, talabostat induces CARD8-mediated pyroptosis in THP-1 and other AML cells, which is independent of NLRP1, indicating that CARD8 can also form inflammasome. 413 , 419 , 420 It has been found that DPP8/9 inhibitors induce pyroptosis in the vast majority of human acute myeloid leukemia (AML) cell lines, and these inhibitors suppress the progression of human AML in mouse models. 162 , 413 What’s more, CARD8 was involved in the pyroptosis of human myeloid cells induced by DPP8/9 inhibitors, which provided a new potential strategy for the treatment of AML.…”

Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier

“…However, UVB irradiation does induce IL-1β release in murine skin, which is mediated by infiltrating professional immune cells (mainly dendritic cells) and not keratinocytes [ 87 ]. These result show the poor conservation of the NLRP1 pathway between human and mouse skin [ 108 ]. Interestingly, 3C proteases and dsRNA only activate human NLRP1, whereas Anthrax Lethal Factor metalloprotease induces cleavage of murine Nlrp1b but not the human form [ 109 ].…”

“…T. gondii infection and Dpp8/9 inhibition with Talabostat (Val-boroPro) commonly activated both murine and human isoforms. Interestingly, Talabostat activates CARD8 in THP-1 cell-lines but triggers NLRP1 activation in keratinocytes, despite both cell types expressing both sensors [ 108 ].…”

“…This leads to skin hyperplasia and formation of keratoacanthoma, the continuous cycles of immune clearance and inflammasome activation may promote the acquisition of oncogenic mutations that facilitate the development of squamous cell carcinoma. This is an interesting association of NLRP1 and skin cancer, reinforced by the fact that the NLRP1 agonist, UVB irradiation, is a primary risk factor for keratinocyte carcinomas [ 96 , 108 , 113 ].…”

Epidermal TRPV4 ion channels regulate UVB induced sunburn by triggering inflammmasome activation and ERK signaling

“…In HPKCs, it has been demonstrated previously that NLRP1 can function as principal inflammasome sensor (31). UVB radiation induces its activation in keratinocytes, which is a key element of the skin's photodermatitis/sunburn response (31,37,38). However other studies have also implicated the NLRP3 inflammasome (29,39).…”