Abstract
Inflammasomes, particularly NLRC4, play crucial roles in immune responses to intracellular bacterial infections. However, gain-of-function mutations in NLRC4 are linked to severe autoinflammatory diseases, including autoinflammation with infantile enterocolitis (AIFEC). AIFEC patients who survive infancy typically have no further intestinal symptoms but retain susceptibility to macrophage activation syndrome (MAS). However, existing mouse models do not adequately replicate the inflammation observed in AIFEC patients. To better understand this, we developed a mouse model capable of conditional expression of the activating V341A mutation in NLRC4 (NLRC4-V341A KI). Global conversion to NLRC4-V341A at the germline resulted in symptoms closely mirroring those of human AIFEC, including severe infantile enterocolitis characterized by heightened intestinal inflammation, disrupted gut epithelium, compromised intestinal barrier integrity, severe diarrhea, and mortality within 10 days post-natally. Additionally, they displayed systemic autoinflammation marked by elevated levels of IL-1β, IL-18, and IL-6, alongside cytopenia and hemophagocytosis. In contrast, conditional conversion to NLRC4-V341A in adulthood caused systemic autoinflammation with only mild enterocolitis, mirroring AIFEC patients. Using this model, we demonstrated that IL-18 and TNF blockade effectively ameliorated AIFEC disease symptoms. Unexpectedly, glucose supplementation has emerged as a promising therapeutic strategy. These findings advance our understanding of AIFEC and illuminate the ways in which inflammasome activation contributes to very early onset inflammatory bowel disease (VEO-IBD) in the developing gut.