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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 re...

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Autores principales: Dewals, Benjamin G., Marillier, Reece G., Hoving, Jennifer C., Leeto, Mosiuoa, Schwegmann, Anita, Brombacher, Frank
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872644/
https://www.ncbi.nlm.nih.gov/pubmed/20502521
http://dx.doi.org/10.1371/journal.pntd.0000689
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author Dewals, Benjamin G.
Marillier, Reece G.
Hoving, Jennifer C.
Leeto, Mosiuoa
Schwegmann, Anita
Brombacher, Frank
author_facet Dewals, Benjamin G.
Marillier, Reece G.
Hoving, Jennifer C.
Leeto, Mosiuoa
Schwegmann, Anita
Brombacher, Frank
author_sort Dewals, Benjamin G.
collection PubMed
description 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.
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spelling pubmed-28726442010-05-25 IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness Dewals, Benjamin G. Marillier, Reece G. Hoving, Jennifer C. Leeto, Mosiuoa Schwegmann, Anita Brombacher, Frank PLoS Negl Trop Dis Research Article 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. Public Library of Science 2010-05-18 /pmc/articles/PMC2872644/ /pubmed/20502521 http://dx.doi.org/10.1371/journal.pntd.0000689 Text en Dewals et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Dewals, Benjamin G.
Marillier, Reece G.
Hoving, Jennifer C.
Leeto, Mosiuoa
Schwegmann, Anita
Brombacher, Frank
IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness
title IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness
title_full IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness
title_fullStr IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness
title_full_unstemmed IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness
title_short IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness
title_sort il-4rα-independent expression of mannose receptor and ym1 by macrophages depends on their il-10 responsiveness
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872644/
https://www.ncbi.nlm.nih.gov/pubmed/20502521
http://dx.doi.org/10.1371/journal.pntd.0000689
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