A Possible Association Between a Nucleotide‐Binding Domain LRR‐Containing Protein Family PYD‐Containing Protein 1 Mutation and an Autoinflammatory Disease Involving Liver Cirrhosis

Abstract

N ucleotide-binding domain leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-containing protein 1 (NLRP1) forms an inflammasome complex with apoptosis-associated speck-like protein containing a caspase recruitment domain and caspase-1. Inflammasome-activated caspase-1 cleaves pro-IL-1β or pro-IL-18 to produce its mature form and induces a type of cell death called pyroptosis through gasdermin D activation. NLRP1 undergoes autoproteolysis within its function-to-find domain (FIIND) to generate N-and C-terminal fragments that remain associated; the liberated C-terminal fragment, including caspase activation and recruitment domain (CARD), triggers inflammasome activation. NLRP1-associated autoinflammatory diseases are caused by genetic alterations of NLRP1, including a FIIND mutation in one case. (1,2) Case PresentationWe previously reported on an atypical case of Papillon-Lefèvre syndrome in an 11-year-old girl with an episode of palmoplantar keratosis and periodontitis; however, she also had liver cirrhosis as one of its unusual symptoms. Any mutation in the cathepsin C gene was not present. (3) Because of Abbreviations: CK-18, cytokeratin 18; FIIND, function-to-find domain; LRR, leucine-rich repeat; NLRP1, nucleotide-binding domain LRRcontaining protein family PYD-containing protein 1; NLRP3, nucleotide-binding domain LRR-containing protein family PYD-containing protein 3; PYD, pyrin domain; SNPs, single-nucleotide polymorphisms.

NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype

“…Accordingly, we found hyper-expression of p16 Ink4a in liver sections of this patient compared to a control liver samples (Fig. 4A), findings that were consistent with the previously reported association of senescence with liver steatosis and cirrhosis (17–20).…”

“…Accordingly, we found hyper-expression of p16 Ink4a in liver sections of this patient compared to a control liver samples (Fig. 4A), findings that were consistent with the previously reported association of senescence with liver steatosis and cirrhosis (17–20). We also evaluated the abundance of senescent-associated proteins in a patient with a biallelic DPP9 rare variants with hypomorphic or lacking alleles that failed to repress NLRP1.…”

Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis

“… 12 Of importance, in patients with cirrhosis who undergo liver transplantation, the serum level of IL‐18 normalized, indicating a key role of the liver in IL‐18 production. 38 Furthermore, IL‐18 has been associated previously with progression of cardiac, 39 pulmonary, 40 and renal fibrosis. 41 , 42 The activation of HSCs is a well‐studied and essential event in fibrogenesis by their transdifferentiation into a proliferative and migratory MFB‐like cell type.…”

“…Interestingly, patients with end‐stage liver disease (Child‐Pugh stage C) presented a decreased level of IL‐18BP and therefore significantly elevated amounts of unbound IL‐18, suggesting a causative role of IL‐18 in the development and progression of liver diseases 12. Of importance, in patients with cirrhosis who undergo liver transplantation, the serum level of IL‐18 normalized, indicating a key role of the liver in IL‐18 production 38. Furthermore, IL‐18 has been associated previously with progression of cardiac,39 pulmonary,40 and renal fibrosis 41,42.…”

The NLRP1 Inflammasome Induces Pyroptosis in Human Corneal Epithelial Cells

“…These patients presented with diffuse skin dyskeratosis, autoinflammation, and arthritis, and were found to have NLRP1 missense mutations (R726W and P1214R). More recently, three additional missense mutations in NLRP1 (A59P, T755N, and P1214L) have been linked with corneal dyskeratosis, 22 juvenile-onset recurrent respiratory papillomatosis (JRRP), 23 and liver cirrhosis, 24 respectively.…”