Abstract
The nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome, which is required for synthesis of interleukin-1β, has been implicated in the pathogenesis of several autoinflammatory syndromes. This review of the literature summarizes the interconnectedness of NALP3 inflammasome with some of these disorders. Familial Mediterranean fever results from a mutation in the Mediterranean fever (MEFV) gene, which encodes the pyrin protein. Previous study results suggest that pyrin suppresses caspase-1 activation, perhaps by competing for the adaptor protein, termed, pyrin domain of apoptosis/speck-like protein containing a caspase-recruitment domain (ACS) which therefore interferes with NALP3 inflammasome activation. The nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome is constitutively activated in cryopyrin-associated periodic syndromes due to gain-of-function mutations resulting from point mutations within the neuronal apoptosis inhibitor protein/class 2 transcription factor/heterokaryon incompatibility/telomerase-associated protein-1 (NACHT) domain of the NALP3 protein. Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is caused by mutations in the genes encoding proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1). These PSTPIP1 mutants are thought to bind to pyrin causing an increase in the pyrin domain of apoptosis/speck-like protein containing a caspase-recruitment domain (ASC) pyroptosome assembly leading to procaspase-1 recruitment and therefore its activation. Hyperimmunoglublinemia D syndrome is caused by mevalonate kinase (MVK) deficiency, which may be affected by protein accumulation that leads to NALP3 inflammasome activation. Tumor necrosis factor receptor–associated periodic syndrome is associated with mutations in the tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene which decreases the level of soluble tumor necrosis factor receptor-1 (TNFR1) leading to neutralization of tumor necrosis factor (TNF)-α. In general, these autoinflammatory disorders have shown a clinical response to interleukin-1 (IL-1) antagonists, suggesting that the NALP3 inflammasome serves a critical role in their pathogenesis.
Highlights
Because of the severity and the wide spectrum of their clinical manifestations, rare autoinflammatory syndromes have garnered significant research attention
This review focused on the underlying molecular mechanisms, clinical presentation and treatment of familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), PAPA syndrome, hyperimmunoglobulinemia D syndrome (HIDS), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
These disorders have demonstrated a good response to IL-1 antagonists, suggesting that the NALP3 inflammasome serves a critical role in the pathogenesis of these autoinflammatory disorders
Summary
Because of the severity and the wide spectrum of their clinical manifestations, rare autoinflammatory syndromes have garnered significant research attention Such syndromes include familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, hyperimmunoglobulinemia D syndrome (HIDS), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS) [1,2]. Because these disorders lead to recurrent and high levels of systemic inflammation, physicians have appropriately attempted to treat such conditions via anti-inflammatory drugs and immunosuppressive agents. By summarizing the basic immunology of the NALP3 inflammasome as well as the manifestations and treatments of these autoinflammatory syndromes, this review strives to elucidate the interconnectedness of the NALP3 inflammasome with the clinical manifestations of these syndromes and their response to immunosuppressive therapies
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