An animal model for autoinflammation with infantile enterocolitis

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