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.