CAPS and NLRP3

Abstract

Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation. Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1β and CAPS-related inflammatory symptoms. Several mechanisms have been identified that are important for the normal regulation of the cryopyrin inflammasome in order to prevent uncontrolled inflammation. Investigators have taken advantage of some of these pathways to develop and apply novel targeted therapies, which have resulted in improved quality of life for patients with this orphan disease.

Keywords: Familial cold autoinflammatory syndrome; Muckle–Wells syndrome; cryopyrin-associated periodic syndromes; inflammasome; neonatal onset multi-system inflammatory disease.

Figure 1.. NLRP3 mutations reported in CAPS

Most CAPS disease-associated mutations are located in exon 3, which codes for the NOD domain, and there are a few mutations in C terminal exons that code for the LRR domain. Infevers; an online database for autoinflammatory mutations - https://infevers.umai-montpellier.fr/) [, –84] was accessed 3/4/19 and all potential CAPS associated mutations associated with a sub-phenotype were included. The presence of multiple mutations coding the same amino acid suggest mutational hotspots (indicated by interrupted line boxes). There is fairly consistent genotype-phenotype correlation indicated by colors: FCAS (blue), FCAS/MWS (purple), MWS (red), MWS/NOMID (brown), NOMID (green), and low penetrance mutations (black). All mutations are numbered according to the second methionine (although many mutation sequences utilize the first methionine which adds two amino acids to the reported variant). Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Neonatal onset multisystemic inflammatory disease (NOMID), nucleotide oligomerization domain (NOD), Leucine rich repeat (LRR)

Figure 2.. Normal and mutant cryopyrin function

Normal activation of the cryopyrin inflammasome in monocytes and macrophages involves 2 signals: Signal 1 involves toll-like receptor (TLR) activation resulting in NFκB mediated expression of inflammasome protein components and pro-cytokines. Signal 2 involves various specific triggers such as nucleic acids, toxins, and crystals resulting in oligomerization of inflammasome protein components including cryopyrin, ASC, pro-caspase-1, NEK7, SGT1, and HSP90 into a multimeric ring like structure. Formation of the inflammation leads to cleavage of caspases, gasdermin-D, and subsequent cleavage pro-IL-1β and pro-IL-18 with release of mature and active cytokines (IL-1β and IL-18) as well as pyroptosis. IL-1β and IL-18 bind to their respective receptors on the same cell resulting in autoinflammation or other cells resulting in a cascade of inflammatory signaling. Inflammasomes may be released from the cells as ASC specks where they may continue to be functional or be taken up by other macrophages. Activation of mutant (yellow dots) cryopyrin inflammasome does not depend on signal 2 resulting inappropriate activation and inflammation. Several therapies (red targets) in the pathway are either available or in development.