An animal model for autoinflammation with infantile enterocolitis

Abstract

Abstract Autoinflammation with infantile enterocolitis (AIFEC) is one of the emerging life-threatening diseases caused by inborn errors of NLRC4 inflammasome. The pathogenicity of AIFEC remains largely unknown and standard therapy is lacking due to rare patient cases and high mortality. To fill the gap, it is urgent to set up an effective animal model for this rare disease. We have recently generated a loxP-flanked NLRC4 V341A conditional knock-in (KI) mouse line where human V341A (GTG to GCG) mutation was introduced into the corresponding mouse Nlrc4coding sequence. When this line is bred with distinct Cre transgenic mice, the KI allele can be expressed globally or cell-type specifically. We bred the KI line with E2a-Cre transgenic mice and got globally expressed V341A KI mice, and the KI mice developed autoinflammation with infantile enterocolitis that recapitulated the symptoms of AIFEC patients. In brief, immunoblot demonstrated KI mice had hyperactivation of NLRC4 inflammasome in gut epithelium and macrophages. The neonatal KI pups had significant intestinal inflammation, accompanied with diarrheal, impaired barrier integrity and dysbiosis. Furthermore, the KI pups had dramatically elevated IL-1β, IL-6 and IL-18 in sera and supernatant of colon explant cultures. Meanwhile, the KI pups exhibited cytopenia, hemophagocytosis, and macrophage hyperactivation. Biochemical assays suggested multi-organ damage in KI mice, including the liver, kidney, and heart, accompanied with hyper serum ferritin level. Without any intervention, the pups died before day 10 postnatally. Taken together, we have established a novel animal model for AIFEC, thus providing a platform to elucidate the pathogenesis of AIFEC and test therapeutic strategies. Startup fund from the Department of pathology at the University of IOWA, NIH R21AG076895, R01 NS104164