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    • In this study we used a

    2018-10-23

    In this study, we used a murine model of Schistosoma japonicum (S. japonicum) to investigate the roles of miR-146a/b, two upregulated miRNAs identified in our previous study (He et al., 2015), in the progression of hepatic schistosomiasis. We found miR-146 was primarily expressed in hepatic macrophages, and inhibited the differentiation of macrophages to M1 cholecystokinin receptor by targeting signal transducer and activator of transcription 1 (STAT1), a crucial molecule in IFN-γ signalling. In addition, a series of Th2 cytokines, including IL-4, IL-10, and IL-13, induced the expression of miR-146b by activating STAT3/6 in macrophages, and thus prevented the differentiation of macrophages into M1 cells.
    Methods
    Results
    Discussion Macrophages have been reported to modulate the initiation, maintenance, and resolution of schistosomiasis through differentiating to various activation states, and therefore, a therapy designed to manipulate macrophage activation could be a relevant approach to treat this chronic disease. However, to date, no well-validated targets have been identified in macrophages in order to treat this disease. In this study, we found that miR-146a/b were primarily expressed in the hepatic macrophages, and that miR-146a/b inhibited the differentiation of macrophages to M1 cells by targeting STAT1. Importantly, we found that various Th2 cytokines, including IL-4, IL-10, and IL-13, could induce macrophages to express miR-146b, but not miR-146a, by activating the promoter of pre-miR-146b gene. Further, these cytokines could potently block the differentiation of macrophages to M1 macrophages, partly by induction of miR-146b. Thus, our data indicated that miR-146 played an important role in the regulation of macrophage activation during hepatic schistosomiasis. Schistosomes are a prime example of a complex multicellular pathogen that survives in the host despite the development of a significant immune response, and understanding how the immune system acts against this parasite is still a daunting challenge. It is well documented that macrophages, key cells of the immune system, play a central role in the immunopathology induced by schistosome eggs by differentiating into various phenotypes. Several studies have highlighted that prompt transition of macrophages from M1 cells to M2 cells is critical for the host to survive in cases of acute schistosomiasis (Herbert et al., 2004), however, little is known about the mechanisms that regulate the transition between macrophage phenotypes. Here, our study implies that miR-146 might be an important mediator in this process, and our data suggest that at the early stage of infection including the migration of the schistosomula and adult worms, the dominant immune response is Th1 type and elevated IFN-γ levels stimulate macrophages to differentiate to M1 cells through activation of STAT1. When the parasites begin to produce eggs, the host immunity switches to a Th2 response and upregulated Th2 cytokines begin to induce the macrophages to differentiate to M2 cells, and meanwhile, these cytokines such as IL-10 and IL-4/13 also induce the expression of miR-146b by activating STAT3/6, which bind to the promoter of the pre-miR-146b gene and initiate transcription. The resulting miR-146b further inhibits the differentiation of M1 macrophages by targeting STAT1 (Fig. 7). Considering the fact that prompt transition of macrophages from M1 cells to M2 cells is critical for host to survive in the acute schistosomiasis, we speculated that miR-146 could be a crucial protective factor for host in the acute stage of infection, and played an important role in the transition from acute to chronic infection. It is worthy to point out that, though we did not explore it in this study, miR-146 might also be involved in the regulation of other immune cells, such as B cells and T cells, which are essential for the development of hepatic schistosomiasis (Pearce and MacDonald, 2002). Schistosomiasis is a debilitating and chronic disease associated with egg-induced inflammation, tissue damage, and subsequent fibrosis. The highly desirable outcome in the treatment of schistosomiasis is to resolve inflammation, reverse fibrosis, and restore normal tissue architecture and function (Barron and Wynn, 2011). Numerous studies have established that M1 macrophages are related to inflammation and tissue damage, but are capable of remodelling the ECMs, while M2 macrophages are essential for hosts to survive the acute phase of infection, but are involved in fibrosis (Barron and Wynn, 2011). Thus, therapies designed to manipulate macrophage activation appear suitable for treating this chronic disease. It is reasonable that development of slightly more M1 than M2 macrophages will be beneficial to provide the greatest degree of protection during infection by minimizing fibrosis, while simultaneously protecting the host from tissue damage. In this study, we have investigated whether miR-146 could manipulate macrophage activation and have a potential for treating schistosomiasis through regulating differentiation of macrophages. S. japonicum infection can elevate the expression of miR-146 that could block differentiation of hepatic macrophages into M1 cells by targeting STAT1. Thus, manipulation of the expression of miR-146 could result in more macrophages differentiating into M1-type, leading to elevated iNOS expression that might attenuate the formation of egg granuloma and fibrosis (Wynn et al., 1995). In addition, the degree of target inhibition imposed by miRNAs always tends to be modest (Ebert and Sharp, 2012), thus, through intervening miRNA expression, the pathway regulated by miRNA in macrophages seemed not to be totally blocked or activated, which is essential for hosts to survive in the course of infection. Therefore, miR-146 appears to be an ideal target to manipulating macrophage activation. However, we have to admit that the hepatic macrophages, defined as CD11b positive cells in this study, might be a mixed population (a proliferating resident macrophages and monocyte-derived macrophages), especially at latter infection time, as a recent study has shown that macrophages in the hepatic granulomas were predominantly derived from monocytes during S. mansoni infection (Nascimento et al., 2014).