Cellular heterogeneity of Schistosoma japonicum egg-induced hepatic granulomas in mice: insights into granuloma formation and evolution

Schistosomiasis morbidity and mortality are primarily driven by hepatic granulomas triggered by parasite eggs with subsequent periportal fibrosis. As a common pathological consequence of various chronic liver injuries, hepatic fibrosis is well-documented. However, the dynamics of cellular composition within the schistosome egg-induced granuloma, particularly the identity and function of key immune cell subsets that orchestrate its formation and evolution, remain poorly resolved. To address this, we combined single-cell RNA sequencing with multiplex immunofluorescence, histopathological analysis, and serological profiling to comprehensively characterize the hepatic immune landscape in a murine model of Schistosoma japonicum infection, and further validated the functional roles of two neutrophil subsets through targeted marker gene knockdown. We found that egg deposition altered hepatic immune cell composition, characterized by extensive neutrophil recruitment and differentiation. Neutrophil recruitment correlated with CXCL2 derived from both an autocrine loop and paracrine signaling by monocytes. Cellular localization analysis of the developmental trajectory of granulomas showed that they progressed from the early Ly6G ^hi F4/80 ^lo Desmin ^lo stage, through the developing Ly6G ^mid F4/80 ^hi Desmin ^mid stage, to the advanced Ly6G ^lo F4/80 ^mid Desmin ^hi stage. In addition, neutrophil subsets display zonal distribution within early granulomas: CD177 ⁺ neutrophils surrounded the eggs, while Ltf ⁺ neutrophils localized to the mid-outer layer. Cd177 knockdown reduced granuloma size and fibrosis, while Ltf suppression increased these pathological features, indicating that CD177 ⁺ and LTF ⁺ neutrophils have opposite effects on granuloma formation. Our findings provide new insight into the cellular complexity of S. japonicum egg-induced granulomas and could help guide the development of novel treatments for liver fibrosis.