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.
Highlights
Schistosomiasis is a severe parasitic disease with more than 200 million people infected worldwide with an estimated 280,000 deaths per annum in sub-Saharan Africa alone [1,2]
In experimental Schistosoma mansoni infection and egginduced inflammation studies with cell type-specific IL4Ra deficient mice, the role of interleukin 4 receptor a-chain (IL-4Ra)-activated alternative macrophages and IL-4Ra-responsive T cells was investigated with focus on the control of hepatic inflammation and granuloma formation
As the major alterations of the immune response depending on IL-4Ra might be restricted to the direct environment surrounding the parasite eggs, we focus in this study on the liver granuloma level to investigate how macrophage- or T cell-specific IL-4Ra responses affect the local responses directed against Schistosoma eggs
Summary
Schistosomiasis is a severe parasitic disease with more than 200 million people infected worldwide with an estimated 280,000 deaths per annum in sub-Saharan Africa alone [1,2]. Infection of macrophage/neutrophil-specific (LysMcreIl4ra2/lox) and T cell-specific (iLckcreIl4ra2/lox) IL-4Ra-deficient mice showed these mice to have high mortality during acute schistosomiasis irrespective of granuloma formation [6,10]. The absence of IL-4Ra-dependent T cell responses resulted in severe hepatotoxicity while an absence of IL-4Ra-activated macrophages was responsible for the development of severe inflammation and damage in both intestine and liver, with a subsequent increase in serum lipopolysaccharide (LPS) levels and aspartate transaminase levels in the serum, respectively [6]. Though the mechanism(s) explaining the high mortality rates observed in LysMcreIl4ra2/lox mice is(are) not fully understood, the observed increased Th1/type in presence of normal Th2/type 2 cytokine and antibody systemic responses could be detrimental for the host survival [6]
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