Recruitment of hepatic macrophages from monocytes is independent of IL-4Ralpha but is associated with ablation of resident macrophages in schistosomiasis.

peer reviewedAlternatively-activated Mphis (AAMphi) accumulate in hepatic granulomas during schistosomiasis and have been suggested to originate in the bone marrow. What is less understood is how these Mphi responses are regulated after S. mansoni infection. Here, we investigated the role of IL-4 receptor alpha-chain (IL-4Ralpha)-signalling in the dynamics of liver Mphi responses. We observed that IL-4Ralpha signalling was dispensable for the recruitment of Ly6C(hi) monocytes and for their conversion into F4/80(hi) CD64(hi) CD11b(hi) Mphi. Moreover, while IL-4Ralpha provided an AAMphi phenotype to liver F4/80(hi) CD64(hi) CD11b(hi) Mphi that was associated with regulation of granuloma formation, it was dispensable for host survival. Resident F4/80(hi) CD64(hi) CD11b(lo) Mphi did not upregulate the AAMphi signature gene Ym1. Rather, resident Mphi nearly disappeared by week 8 after infection and artificial ablation of resident Mphi in CD169(DTR) mice did not affect the response to S. mansoni infection. Interestingly, ablation of CD169(+) cells in naive mice resulted in the accumulation of F4/80(hi) CD64(hi) CD11b(hi) Mphi, which was amplified when ablation occurred during schistosomiasis. Altogether, our results suggest the ablation of resident KCs after S. mansoni infection to be associated with the recruitment and accumulation of F4/80(hi) CD64(hi) CD11b(hi) Mphi with lyz2-dependent IL-4Ralpha contributing to the regulation of granuloma inflammation but being dispensable for host survival. This article is protected by copyright. All rights reserved