IL-4Ra-dependent macrophage responses in the liver during murine schistosomiasis

During Schistosoma mansoni infection in mice, IL-4 receptor-dependent alternatively activated macrophages (aaMφ) response mediate host protection. Here, we used LysMcreIl4ra−/lox mice to determine whether the absence of Mφ-specific IL-4 receptor signalling modifies the dynamics of Mφ responses in liver granulomas after S. mansoni infection. Liver inflammatory response was investigated after low-dose S. mansoni infection. We observed significantly increased total leukocyte numbers in the liver by week 8 in LysMcreIl4ra−/lox mice while mice survived the infection similarly to littermate controls. Over the course of infection, we observed that CD11blowMerTK+CD64+ resident Küpffer cells (KCs) were severely reducing in term of numbers independently of IL-4Rα signalling. While KCs lowered, Ly6Chi monocytes were recruited in the liver from 6 weeks pi, proliferate strongly at week 8 and acquire CD64 expression. The number of Ly6Chi recruited monocytes were significantly higher in LysMcreIl4ra−/lox mice than littermate controls. From 8 weeks pi, CD11blow KCs seemed to be replaced by CD11bhighMerTK+CD64+F4/80+ Mφ, probably derived from recruited Ly6Chi monocytes. At week 8 pi, expression of Ym1 and Relm-alpha was significantly reduced in hepatic CD11bhigh Mφ of LysMcreIl4ra−/lox mice compared to littermate controls. These results suggest that recruited monocytes differentiate into Mφ at the cost of resident KCs independently of IL-4Rα and validate the use of LysMcreIl4ra−/lox mice to study IL-4Rα-dependent activation of monocyte-derived granuloma Mφ during schistosomiasis.