IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness

IL-4Rα-dependent responses are essential for granuloma formation and host survival during acute schistosomiasis. Previously, we demonstrated that mice deficient for macrophage-specific IL-4Rα (LysM(cre)Il4ra(−/lox)) developed increased hepatotoxicity and gut inflammation; whereas inflammation was restricted to the liver of mice lacking T cell-specific IL-4Rα expression (iLck(cre)Il4ra(−/lox)). In the study presented here we further investigated their role in liver granulomatous inflammation. Frequencies and numbers of macrophage, lymphocyte or granulocyte populations, as well as Th1/Th2 cytokine responses were similar in Schistosoma mansoni-infected LysM(cre)Il4ra(−/lox) liver granulomas, when compared to Il4ra(−/lox) control mice. In contrast, a shift to Th1 responses with high IFN-γ and low IL-4, IL-10 and IL-13 was observed in the severely disrupted granulomas of iLck(cre)Il4ra(−/lox) and Il4ra(−/−) mice. As expected, alternative macrophage activation was reduced in both LysM(cre)Il4ra(−/lox) and iLck(cre)Il4ra(−/lox) granulomas with low arginase 1 and heightened nitric oxide synthase RNA expression in granuloma macrophages of both mouse strains. Interestingly, a discrete subpopulation of SSC(high)CD11b(+)I-A/I-E(high)CD204(+) macrophages retained expression of mannose receptor (MMR) and Ym1 in LysM(cre)Il4ra(−/lox) but not in iLck(cre)Il4ra(−/lox) granulomas. While aaMφ were in close proximity to the parasite eggs in Il4ra(−/lox) control mice, MMR(+)Ym1(+) macrophages in LysM(cre)Il4ra(−/lox) mice were restricted to the periphery of the granuloma, indicating that they might have different functions. In vivo IL-10 neutralisation resulted in the disappearance of MMR(+)Ym1(+) macrophages in LysM(cre)Il4ra(−/lox) mice. Together, these results show that IL-4Rα-responsive T cells are essential to drive alternative macrophage activation and to control granulomatous inflammation in the liver. The data further suggest that in the absence of macrophage-specific IL-4Rα signalling, IL-10 is able to drive mannose receptor- and Ym1-positive macrophages, associated with control of hepatic granulomatous inflammation.