Abstract
Accumulation of M2 macrophages in the liver, within the context of a strong Th2 response, is a hallmark of infection with the parasitic helminth, Schistosoma mansoni, but the origin of these cells is unclear. To explore this, we examined the relatedness of macrophages to monocytes in this setting. Our data show that both monocyte-derived and resident macrophages are engaged in the response to infection. Infection caused CCR2-dependent increases in numbers of Ly6Chi monocytes in blood and liver and of CX3CR1+ macrophages in diseased liver. Ly6Chi monocytes recovered from liver had the potential to differentiate into macrophages when cultured with M-CSF. Using pulse chase BrdU labeling, we found that most hepatic macrophages in infected mice arose from monocytes. Consistent with this, deletion of monocytes led to the loss of a subpopulation of hepatic CD11chi macrophages that was present in infected but not naïve mice. This was accompanied by a reduction in the size of egg-associated granulomas and significantly exacerbated disease. In addition to the involvement of monocytes and monocyte-derived macrophages in hepatic inflammation due to infection, we observed increased incorporation of BrdU and expression of Ki67 and MHC II in resident macrophages, indicating that these cells are participating in the response. Expression of both M2 and M1 marker genes was increased in liver from infected vs. naive mice. The M2 fingerprint in the liver was not accounted for by a single cell type, but rather reflected expression of M2 genes by various cells including macrophages, neutrophils, eosinophils and monocytes. Our data point to monocyte recruitment as the dominant process for increasing macrophage cell numbers in the liver during schistosomiasis.
Highlights
Schistosomiasis is a complex multiorgan disease caused by infection with helminth parasites of the genus Schistosoma, and characterized by the development of granulomatous lesions around parasite eggs trapped within organs such as the liver and intestine
Schistosomiasis is an important neglected tropical disease caused by parasitic worms of the genus Schistosoma
During infection with S. mansoni, parasite eggs become trapped in the liver and elicit granulomatous inflammation characterized by accumulations of immune cells intermixed with liver cells around the eggs
Summary
Schistosomiasis is a complex multiorgan disease caused by infection with helminth parasites of the genus Schistosoma, and characterized by the development of granulomatous lesions around parasite eggs trapped within organs such as the liver and intestine. Granulomas are, by definition, macrophage-rich, but in schistosomiasis are recognized to contain substantial numbers of additional cells such as eosinophils, reflecting the fact that infection is associated with the development of a marked Th2 response [1]. Expanded macrophage populations in inflammatory sites are thought to arise from the recruitment of circulating inflammatory (Ly6Ch) monocytes from the bloodstream, and the in situ differentiation of these cells into macrophages [2]. Little is known about the contribution of monocytes to inflammation during schistosomiasis. This is an interesting issue because recent reports have stressed that during Th2-dominated responses to nematode helminth parasites, macrophage rich inflammatory infiltrates arise as a result of IL-4-driven local macrophage proliferation, and not monocyte recruitment [5,6]. M2 macrophages are implicated in wound healing, metabolic homeostasis of adipose tissue, and in protective immunity to helminths, where type 2 immunity dominates [8,9]
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