Ly6C ^hi Monocyte Recruitment Is Responsible for Th2 Associated Host-Protective Macrophage Accumulation in Liver Inflammation due to Schistosomiasis

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 Ly6C ^hi monocytes in blood and liver and of CX ₃CR1 ⁺ macrophages in diseased liver. Ly6C ^hi 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 CD11c ^hi 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.

Author Summary

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. This inflammation is responsible for disease symptoms, but also plays an important role in protecting the host against liver damage that can be caused by egg products. Granulomas, by definition, contain a significant number of macrophages (phagocytic cells of the immune system). Recent work has emphasized that macrophage numbers in inflammation can increase due either to recruitment of precursor cells (called monocytes) from the blood, or as a result of proliferation of tissue-resident macrophages. Local proliferation has been noted in other worm infections, during which the immune response is Th2-like and IL-4 produced by Th2 cells promotes macrophages to become “alternatively (or M2) activated”. We examined the origin of the increased numbers of macrophages in liver inflammation due to schistosomiasis, in which there is also a prominent Th2 response. We found that the cells mostly originated from monocytes recruited into the tissue from the blood. This response was critical for host survival during infection.