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

Abstract

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.

Inflammasome as an early pathophysiological phenomenon of inflammation in skin diseases and other pathologies

“…Воспаление не является единственным нисходящим эффектом активации инфламмасом, так как известно также их участие в представлении антигенов, транскрипции [4], посттранскрипционной и посттрансляционной регуляции [18,19], клеточном старении и смерти [37], а также канцерогенезе [9]. При комбинированных нисходящих эффектах в случаях, если наблюдается неконтролируемая гиперактивация, возможно развитие аутовоспалительных [38][39][40], аутоиммунных [41,42], аллергических болезней [43,44] и рака [11,45] (таблица). Классическими, нередко встречающимися расстройствами, которые ассоциированы с инфламмасомами, являются аутовоспалительные патологии (например, семейная средиземноморская лихорадка, криопиринопатии, периодическая болезнь, болезнь Стилла и др.)…”

The gasdermins: a pore-forming protein family expressed in the epidermis

“…Single nucleotide polymorphisms (SNPs) of NLRP1 are associated with (auto)inflammatory diseases affecting mainly the skin, such as vitiligo ( 43 , 44 , 53 ). Gain-of-function mutations of NLRP1 cause inflammatory skin syndromes, which predispose patients to the development of squamous cell carcinoma, a type of keratinocyte-derived skin cancer ( 54 , 55 ). The NLRP1 pathway is poorly conserved in mice ( 56 ).…”