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

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Abstract
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 (LysMcreIl4ra−/lox) developed increased hepatotoxicity and gut inflammation; whereas inflammation was restricted to the liver of mice lacking T cell-specific IL-4Rα expression (iLckcreIl4ra−/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 LysMcreIl4ra−/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 iLckcreIl4ra−/lox and Il4ra−/− mice. As expected, alternative macrophage activation was reduced in both LysMcreIl4ra−/lox and iLckcreIl4ra−/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 SSChighCD11b+I-A/I-EhighCD204+ macrophages retained expression of mannose receptor (MMR) and Ym1 in LysMcreIl4ra−/lox but not in iLckcreIl4ra−/lox granulomas. While aaMφ were in close proximity to the parasite eggs in Il4ra−/lox control mice, MMR+Ym1+ macrophages in LysMcreIl4ra−/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 LysMcreIl4ra−/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. Schistosomiasis is a tropical disease caused by one of the species of the parasitic worm Schistosoma which infects over 200 million people worldwide. Signalling via the IL-4 receptor alpha (IL-4Rα), which is the common receptor chain for the ligands IL-4 and IL-13, is essential for inducing protective Type 2 immune response and granuloma formation in response to the parasite eggs. In experimental Schistosoma mansoni infection and egg-induced inflammation studies with cell type-specific IL-4Rα deficient mice, the role of IL-4Rα-activated alternative macrophages (aaMφ) and IL-4Rα-responsive T cells was investigated with focus on the control of hepatic inflammation and granuloma formation. Interestingly, aaMφ were not essential for the cellular composition or the Th1/Th2 cytokine profile in liver granulomas. In contrast, IL-4Rα-dependent T cell responses were important for predominant Th2 and IL-10 responses, as well as the presence of aaMφ in the granulomas, avoiding major disruption in the granuloma cell composition. Moreover, a macrophage subpopulation was identified and those cells expressed the two aaMφ markers, mannose receptor- and Ym1 in an IL-4Rα-independent but IL-10-dependent manner. These cells might be involved in the control of inflammation.

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