The following is a summary of “NLRP3 leucine-rich repeats control induced and spontaneous inflammasome activation in cryopyrin-associated periodic syndrome,” published in the JANUARY 2023 issue of Allergy & Immunology by Theodoropoulou, et al.

A collection of uncommon autoinflammatory disorders known as the cryopyrin-associated periodic syndromes (CAPS) are brought on by gain-of-function mutations in the NLRP3 gene. Leucine-rich repeats (LRR) domain of NLRP3 is prone to substantial alternative splicing and has a highly conserved exonic structure. Chronic inflammation in CAPS is caused by aberrant NLRP3 inflammasome assembly; however, the mechanisms governing inflammasome activity were unknown. For a study, researchers sought to define the function of LRR in inflammasome activation to unravel the processes controlling NLRP3-mediated autoinflammation in human illness.

To understand the pattern of NLRP3 splicing in human monocytes, they studied sequence-read archive data. They also looked into the function of each LRR-coding exon in the regulation of the inflammasome in genetically altered U937 cells that mimic CAPS and healthy settings.

They found many NLRP3 splice variants in human primary cells and monocytic cell lines, including 2 that have not previously been characterized. The observation that lipopolysaccharides have an impact on the prevalence of certain splice variants raised the possibility that they control NLRP3 activation by influencing alternative splicing. In the setting of the agonist molecule nigericin activating wild-type NLRP3 as well as in a model of CAPS-mediated NLRP3 inflammasome construction, they demonstrated that exons 4, 5, 7, and 9 are crucial for inflammasome activity. Further evidence that alternative splicing may control the recruitment of proteins that assist inflammasome formation comes from the reduced SGT1-NLRP3 interaction in nonfunctional variants.

The results showed the role of the LRR domain in inflammasome function and implied that controlling LRR exon use in NLRP3 was enough to prevent inflammasome formation in CAPS.

Reference: jacionline.org/article/S0091-6749(22)01168-X/fulltext