A Novel Murine Model of Hemophagocytic Lymphohistiocytosis‐Like Inflammation in ZNFX1 Deficiency

Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory syndrome characterized by persistent activation of lymphocytes and macrophages. Recently, deleterious autosomal recessive mutations in ZNFX1 were reported to predispose pediatric patients to HLH‐like disease upon viral trigger. The objective of this study was to assess the suitability of Znfx1‐mutant (Znfx1 ᵐᵘᵗ ) mice infected with lymphocytic choriomeningitis virus (LCMV) as a model of HLH‐like inflammation observed in patients. Following LCMV infection, Znfx1 ᵐᵘᵗ mice were monitored for pathophysiological signs of HLH, and their cells were immunophenotyped. Furthermore, functional assays were performed in vitro on T cells and bone marrow‐derived macrophages (BMDMs) to assess the cells’ response to stimuli. Our experiments highlighted several hallmark features of HLH‐like inflammation in Znfx1 ᵐᵘᵗ mice. Immunophenotyping revealed more pronounced T cell expansion and type‐1 helper (Th1) polarization in LCMV‐infected Znfx1 ᵐᵘᵗ mice. Znfx1 ᵐᵘᵗ macrophages infiltrated the liver to a greater extent upon infection and produced greater levels of cytokines in vitro in the absence of stimulation, suggesting that these cells have a major role in driving inflammation. This novel murine model of HLH‐like inflammation mirrors key aspects of the immune dysregulation observed in patients, providing a valuable tool for studying disease mechanisms in ZNFX1 deficiency.