NLRP1 Inflammasome

Inflammasomes are instruments of the innate immune system that are responsible for the activation of inflammatory reactions. Inflammasomes are cytosolic (intracellular) multi-protein complexes (Martinon F et al. 2002), which are predominantly found in immune cells, such as dendritic cells and macrophages, but also in epithelia of the skin and mucous membranes (intestinal and urinary bladder epithelia). Activation of the inflammasome promotes the proteolytic cleavage, maturation and secretion of the pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as the cleavage of gas dermin D. The N-terminal fragment resulting from gasdermin D cleavage, triggers a pro-inflammatory form of programmed cell death of pyroptosis and is responsible for the secretion of mature cytokines, presumably through the formation of pores in the plasma membrane (Broz P et al. 2016). In addition, inflammasomes can also trigger a special form of programmed cell death, PANOptosis, which has essential features of apoptosis, pyroptosis and necroptosis (Zhuang L et al.2023).

Inflammasome activation is triggered by different types of cytosolic pattern recognition receptors (PRRs), either microbe-derived (pathogen-associated molecular patterns/PAMPs) or host cell-derived (damage-associated molecular patterns/DAMPs). The pattern recognition receptors involved in inflammasomes include so-called NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors) as well as AIM2 (absent in melanoma 2), IFI16 (IFN-inducible protein 16) and pyrin (Broz P et al. 2016).

The inflammasome receptors interact with the adaptor protein ASC via their caspase activation and recruitment domain (CARD) or via the pyrin domain (PYD), which then activates caspase-1 via its CARD domain by proteolytic cleavage (Broz P et al. 2016). Finally, the activated caspase-1 cleaves the immature pro-inflammatory cytokines pro-IL-1beta and pro-IL-18 as well as gas dermin D into their active end stages. IL 1beta and IL 18 in particular are responsible for inflammatory signaling and pyroptotic cell death.

In addition to these so-called canonical inflammasomes, non-canonical inflammasome complexes have also been described that act independently of caspase-1. In animal experiments, non-canonical inflammasomes can be activated by direct recognition of cytosolic bacterial lipopolysaccharide (LPS). In human cells, the corresponding caspases of the non-canonical inflammasome are caspase 4 and caspase 5 (Broz P et al. 2016).

So far, inflammasomes have mainly been detected in professional immune cells of the innate immune system, such as macrophages and neutrophils. However, it is now known that inflammasome components are expressed in epithelial barrier tissues (Winsor N et al. 2019). In the case of dysregulation of inflammasome activation, this can lead to significant disorders of innate immunity, chronic inflammatory states, tumor formation, metabolic and neurodegenerative diseases (Ippagunta SK et al. 2011).

NLRP1 is an acronym for "NACHT domain, leucine-rich repeat, pyrin domains", a key protein of the inflammasome. In addition to NOD and LRR, NLRP1 contains a pyrin domain (PYD) at its N-terminus and a FIIND motif and a CARD at its C-terminus, which distinguishes it from the other inflammasomes. Upon activation, the C-terminal CARD interacts with the CARD of procaspase-1 or procaspase-5, while its N-terminal PYD interacts homotypically with the PYD of the adapter protein ASC, whose CARD can then recruit another pro-caspase-1. The general recruitment and cleavage of procaspase-1 can then activate all downstream caspase-1 signaling pathways.

Polymorphisms in the NLRP1 gene are associated with a familial form of vitiligo.

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