NLRP1 Inflammasome Activation in Keratinocytes: Increasing Evidence of Important Roles in Inflammatory Skin Diseases and Immunity

Fenini, Gabriele; Karakaya, Tugay; Hennig, Paulina; Filippo, Michela Di; Slaufova, Marta; Beer, Hans‐Dietmar

doi:10.1016/j.jid.2022.04.004

Cited by 18 publications

(25 citation statements)

References 124 publications

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“…NLRP1 is one of the major inflammasomes modulating the inflammatory response of the skin and so correlated to a variety of cutaneous condition [ 23 ]. Although NLRP1 has been the first inflammasome to be discovered, multiple questions regarding its activation are still unanswered.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, reactive oxygen species (ROS) associated to pollutants exposure, have been identified as crucial figures in triggering the activation of certain types of inflammasomes [ [17] , [18] , [19] , [20] ]. NLRP1 that is the most present inflammasome within the human skin has been reported to exacerbate the inflammatory status displayed in many skin pathologies such as vitiligo, atopic dermatitis, psoriasis, acne, carcinogenesis, melanoma [ 4 , [21] , [22] , [23] ] and also be particularly susceptible to environmental stimuli such as UV radiation. However, despite other well-known and characterized inflammasomes, very few is known about the mechanism behind NLRP1 activation in humans.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ubiquitination as a key regulatory mechanism for O3-induced cutaneous redox inflammasome activation

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ubiquitination as a key regulatory mechanism for O3-induced cutaneous redox inflammasome activation

et al. 2022

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“…Other members of the IL-1 family can have roles in tumorigenesis, too. It is believed that IL-33 is biologically active in its pro-form [ 101 ], although more potent when cleaved [ 102 ], and has pro-tumorigenic activity [ 11 , 87 , 88 ], particularly at early stages of cancer development [ 103 , 104 ]. ProIL-36, on the other hand, requires proteolytic activation by different proteases in order to be active and is associated with the inhibition of tumor development [ 76 , 77 ].…”

Section: Inflammasomes and Cancermentioning

confidence: 99%

“…However, the roles of human NLRP1 are only poorly conserved between humans and mice, demonstrating that the NLRP1 is a relatively young evolutionary pathway [ 101 ]. Mechanistically, only human NLRP1 but not murine Nlrp1b is activated by dsRNA, ORF45, UVB, and the ribotoxic stress response [ 102 , 114 , 115 , 125 ].…”

Section: The Nlrp1 Inflammasomementioning

confidence: 99%

“…Single nucleotide polymorphisms (SNPs) of the NLRP1 gene are associated with different (auto)inflammatory diseases, which mainly affect the skin, including vitiligo, Addison’s disease, and NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis) [ 101 , 129 , 130 , 131 ]. Furthermore, germline gain-of-function mutations of NLRP1 cause two rare inflammatory skin diseases, MSPC (multiple self-healing palmoplantar carcinoma) and FKLC (familial keratosis lichenoides chronica) [ 108 ].…”

Section: The Nlrp1 Inflammasomementioning

confidence: 99%

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NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development

Filippo

Hennig

Karakaya

et al. 2022

IJMS

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Protein complexes termed inflammasomes ensure tissue protection from pathogenic and sterile stressors by induction of inflammation. This is mediated by different caspase-1-induced downstream pathways, including activation of the pro-inflammatory cytokines proIL-1β and -18, induction of a lytic type of cell death, and regulation of the release of other pro-inflammatory molecules. Aberrant inflammasome activation underlies the pathology of numerous (auto)inflammatory diseases. Furthermore, inflammasomes support or suppress tumor development in a complex cell-type- and stage-dependent manner. In human keratinocytes and skin, NLRP1 is the central inflammasome sensor activated by cellular perturbation induced, for example, by UVB radiation. UVB represents the main inducer of skin cancer, which is the most common type of malignancy in humans. Recent evidence demonstrates that activation of NLRP1 in human skin supports the development of cutaneous squamous cell carcinomas (cSCCs) by inducing skin inflammation. In contrast, the NLRP1 inflammasome pathway is restrained in established cSCCs, suggesting that, at this stage, the protein complex has a tumor suppressor role. A better understanding of the complex functions of NLRP1 in the development of cSCCs and in general of inflammasomes in cancer might pave the way for novel strategies for cancer prevention and therapy. These strategies might include stage-specific modulation of inflammasome activation or its downstream pathways by mono- or combination therapy.

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Autoinflammatory Keratinization Diseases—The Concept, Pathophysiology, and Clinical Implications

Blicharz,

Czuwara,

Rudnicka

et al. 2023

Clinic Rev Allerg Immunol

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Recent advances in medical genetics elucidated the background of diseases characterized by superficial dermal and epidermal inflammation with resultant aberrant keratosis. This led to introducing the term autoinflammatory keratinization diseases encompassing entities in which monogenic mutations cause spontaneous activation of the innate immunity and subsequent disruption of the keratinization process. Originally, autoinflammatory keratinization diseases were attributed to pathogenic variants of CARD14 (generalized pustular psoriasis with concomitant psoriasis vulgaris, palmoplantar pustulosis, type V pityriasis rubra pilaris), IL36RN (generalized pustular psoriasis without concomitant psoriasis vulgaris, impetigo herpetiformis, acrodermatitis continua of Hallopeau), NLRP1 (familial forms of keratosis lichenoides chronica), and genes of the mevalonate pathway, i.e., MVK, PMVK, MVD, and FDPS (porokeratosis). Since then, endotypes underlying novel entities matching the concept of autoinflammatory keratinization diseases have been discovered (mutations of JAK1, POMP, and EGFR). This review describes the concept and pathophysiology of autoinflammatory keratinization diseases and outlines the characteristic clinical features of the associated entities. Furthermore, a novel term for NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) describing the spectrum of autoinflammatory keratinization diseases secondary to NLRP1 mutations is proposed.

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NLRP1 Inflammasome Activation in Keratinocytes: Increasing Evidence of Important Roles in Inflammatory Skin Diseases and Immunity

Cited by 18 publications

References 124 publications

Ubiquitination as a key regulatory mechanism for O3-induced cutaneous redox inflammasome activation

Ubiquitination as a key regulatory mechanism for O3-induced cutaneous redox inflammasome activation

NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development

Autoinflammatory Keratinization Diseases—The Concept, Pathophysiology, and Clinical Implications

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