Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4 mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4 intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as , and predominated in neutrophils, whereas and were distinctly epithelial. Demonstrating the importance of free IL-18, transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4 mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.

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Key Points A phenotype with albinism, early-onset seizures, neurodevelopmental delay, infection susceptibility, and neutropenia is caused by AP3D1 mutations. AP3δ deficiency destabilizes the AP3 complex and defines a novel type of Hermansky-Pudlak syndrome with severe neurologic involvement.

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