A novel knock-in mouse model of CAPS that develops amyloidosis: therapeutic efficacy of proton pump inhibitors.

Abstract

BACKGROUND\nCryopyrin associated periodic syndromes (CAPS) are a group of autoinflammatory diseases linked to gain-of-function mutations in the NLRP3 gene which cause uncontrolled IL-1β secretion. Proton pump inhibitors (PPIs), commonly used as inhibitors of gastric acid production, also display anti-inflammatory properties, protect mice from sepsis, and prevent IL-1β secretion by CAPS monocytes.\n\n\nOBJECTIVE\nTo develop a novel NLRP3 knock-in (KI) mouse model of CAPS to study amyloidosis, a severe CAPS complication, and test novel therapeutic approaches.\n\n\nMETHODS\nWe generated KI mice by engineering the N475K mutation associated with CAPS phenotype into the mouse Nlrp3 gene.KI and Wild Type (WT) mice received PPIs or phosphate-buffered saline (PBS) intraperitoneally and were analyzed for survival, inflammation, cytokine secretion, and amyloidosis development.\n\n\nRESULTS\nMutant NLRP3 KI mice displayed features that recapitulate the immunological and clinical phenotype of CAPS. They showed systemic inflammation with high levels of serum pro-inflammatory cytokines, inflammatory infiltrates in various organs and amyloid deposits in the spleen, liver and kidneys. TLR-stimulated macrophages from KI mice secreted high levels of IL-1β, IL-18 and IL-1α but low amounts of interleukin-1 receptor antagonist (IL-1Ra).Treatment of KI mice with PPIs had a clear clinical impact showing a reduction of inflammatory manifestations, regression of amyloid deposits, and normalization of pro- and anti-inflammatory cytokine production by macrophages.\n\n\nCONCLUSION\nNLRP3 KI mice displayed a CAPS phenotype with many characteristics of autoinflammation, including amyloidosis. The therapeutic effectiveness of PPIs associated with a lack of toxicity indicates that these drugs could represent relevant adjuvants to the anti-IL-1 drugs in CAPS and other IL-1 driven diseases.