Abstract
Fasciola hepatica, also known as the liver fluke, is a trematode that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. This parasite immunoregulates the host immune system by inducing a strong Th2 and regulatory T immune response by immunomodulating dendritic cell (DC) maturation and alternative activation of macrophages. In this paper, we show that F. hepatica infection in mice induces the upregulation of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that regulates the host inflammatory response. We show and characterize two different populations of antigen presenting cells that express HO-1 during infection in the peritoneum of infected animals. Cells that expressed high levels of HO-1 expressed intermediate levels of F4/80 but high expression of CD11c, CD38, TGFβ, and IL-10 suggesting that they correspond to regulatory DCs. On the other hand, cells expressing intermediate levels of HO-1 expressed high levels of F4/80, CD68, Ly6C, and FIZZ-1, indicating that they might correspond to alternatively activated macrophages. Furthermore, the pharmacological induction of HO-1 with the synthetic metalloporphyrin CoPP promoted F. hepatica infection increasing the clinical signs associated with the disease. In contrast, treatment with the HO-1 inhibitor SnPP protected mice from parasite infection, indicating that HO-1 plays an essential role during F. hepatica infection. Finally, HO-1 expression during F. hepatica infection was associated with TGFβ and IL-10 levels in liver and peritoneum, suggesting that HO-1 controls the expression of these immunoregulatory cytokines during infection favoring parasite survival in the host. These results contribute to the elucidation of the immunoregulatory mechanisms induced by F. hepatica in the host and provide alternative checkpoints to control fasciolosis.
Highlights
Fasciolosis, a helminth infection caused by Fasciola hepatica, is of paramount importance due to its wide spectrum of definitive hosts [1] and its worldwide distribution [2] affecting both livestock and human health
We show that the pharmacological induction of HO-1 with the synthetic metalloporphyrin CoPP promotes F. hepatica infection increasing the clinical signs associated with the disease, such as liver damage
We show that HO-1 is a key immunoregulatory molecule during F. hepatica infection and that promotes infection and liver damage
Summary
Fasciolosis, a helminth infection caused by Fasciola hepatica, is of paramount importance due to its wide spectrum of definitive hosts [1] and its worldwide distribution [2] affecting both livestock and human health. Several studies have independently demonstrated that F. hepatica-derived molecules inhibit or decrease dendritic cell (DC) activation, which results in the induction of a tolerogenic phenotype [3,4,5,6,7]. We have demonstrated that DCs from mice infected with F. hepatica have a semi-mature phenotype that is characterized by low MHC II and CD40 expression, high secretion of the immunoregulatory cytokine IL-10, and the ability to differentiate and expand IL-10-producing CD4 T cells [8]. Different groups have reported that F. hepatica-derived molecules modulate macrophage activation, inducing the alternative activation of IL-10-producing macrophages [9, 10] and inhibiting the production of proinflammatory cytokines, such as IL-1β [11], IL-10 [12], Arg-1, PDL-1 [13], and PDL-2 [14, 15]. It has been hypothesized that F. hepatica may modulate both macrophages and DC function and fate as a mean to control its pathogenesis and survival in the infected hosts
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