IL-4R[alpha]-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness e689

• Published in: PLoS neglected tropical diseases Vol. 4; no. 5
• Main Authors: Dewals, Benjamin G, Marillier, Reece G, Hoving, Jennifer C, Leeto, Mosiuoa, Schwegmann, Anita, Brombacher, Frank
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 01.05.2010
• Subjects: Cytokines; Immune system; Infections; Lymphocytes; Medical research; Mortality; Nitric oxide; Parasites; Parasitic diseases; Rodents; Studies; Tropical diseases; Granuloma; Schistosoma mansoni; Interleukin-10; Mannose-Binding Lectins; T-Lymphocytes; Lectins, C-Type; Liver; beta-N-Acetylhexosaminidases; Male; Receptors, Cell Surface; Macrophages; Macrophage Activation; Mice, Knockout; Schistosomiasis mansoni; Animals; Lectins; Female; Mice; Mice, Inbred BALB C
• ISSN: 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0000689

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.