Cellular heterogeneity of hepatic granuloma formation and evolution in murine schistosomiasis japonica.

Abstract

Schistosomiasis morbidity and mortality are primarily driven by egg-triggered granulomas with subsequent fibrosis. However, the dynamics of cellular composition within these granulomas, particularly the identity and function of key immune cells that orchestrate their formation and evolution, remain poorly understood. Here, we combine single-cell RNA sequencing with multiplex immunofluorescence to characterize the hepatic immune landscape in Schistosoma japonicum-infected mice and further validate the functional roles of two neutrophil subsets. We find that eggs alter hepatic immune cell composition, which is characterized by extensive neutrophil recruitment and differentiation. Neutrophil recruitment correlates with CXCL2 derived from both an autocrine loop and paracrine signaling from monocytes. Cellular localization analysis reveals that granulomas progress through three distinct developmental stages: early Ly6G^hiF4/80^loDesmin^lo, developing Ly6G^midF4/80^hiDesmin^mid, and advanced Ly6G^loF4/80^midDesmin^hi. Neutrophil subsets display a zonal distribution within granulomas, with CD177⁺ neutrophils surrounding the eggs and Ltf⁺ neutrophils localizing to the mid-outer layer. Cd177 knockdown reduces granuloma size and fibrosis, whereas Ltf suppression increases these pathological features, indicating that CD177 and LTF exert opposite effects on granuloma formation. Our findings provide new insights into the cellular complexity of S. japonicum egg-induced granulomas and may help guide the development of novel therapies for liver fibrosis.