Thioredoxin Peroxidase Secreted byFasciola hepaticaInduces the Alternative Activation of Macrophages

Abstract

Alternatively activated macrophages (AAM) are primarily associated with the chronic stages of parasitic infections and the development of a polarized Th2 response. We have shown that Fasciola hepatica infection of BALB/c mice induces a polarized Th2 response during both the latent and chronic stage of disease. The activation status of macrophages was analyzed in this model of helminth infection by evaluating the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arg1. AAM were recruited to the peritoneum of mice within 24 h of F. hepatica infection and after intraperitoneal injection of parasite excretorysecretory (ES) products. Administration of a recombinant antioxidant thioredoxin peroxidase (TPx), which is contained within the ES products, also induced the recruitment of AAM to the peritoneum. In vitro studies showed that this recombinant TPx directly converts RAW 264.7 macrophages to an alternatively activated phenotype characterized by the production of high levels of interleukin-10 (IL-10), prostaglandin E 2 , corresponding with low levels of IL-12. Our data suggest that the Th2 responses induced by the helminth F. hepatica are mediated through the secretion of molecules, one of which is TPx, that induce the recruitment and alternative activation of macrophages.

Characterization of the antioxidant enzyme, thioredoxin peroxidase, from the carcinogenic human liver fluke, Opisthorchis viverrini

“…We performed similar experiments to those described by Donnelly et al but with recombinant Ov-TPx-1, and did not detect any bias towards a particular T helper cell response (not shown), despite the fact that our recombinant protein was properly folded and that O. viverrini induces a predominantly Th2 response, at least in hamsters [30]. Absence of glycosylation seems not to affect the Th2 response since recombinant F. hepatica TPx produced in E. coli (without glycosylation) did induce a Th2 bias [29]. O. viverrini molecules other than TPx may therefore be involved in immunomodulation.…”

“…TPx in F. hepatica ES products induced the recruitment and alternative activation of macrophages, associated with the development of a polarized T helper type 2 immune response [29]. We performed similar experiments to those described by Donnelly et al but with recombinant Ov-TPx-1, and did not detect any bias towards a particular T helper cell response (not shown), despite the fact that our recombinant protein was properly folded and that O. viverrini induces a predominantly Th2 response, at least in hamsters [30].…”

Alternatively activated macrophages in helminth infections

“…AAMΦs are observed in a variety of helminth infections, including Th2-type immune responses to Schistosoma mansoni [2], Heligmosomoides polygyrus [3], Nippostrongylus brasiliensis [4], Taenia crassiceps [5], Trichinella spiralis [6], Fasciola hepatica [7], Ascaris suum [8], and filarial parasites [9]. A number of markers are used to identify AAMΦs ( Figure 1).…”

“…The trematode F. hepatica induces an IL-4-dependent Th2-type response, and recent studies indicate that AAMΦs are recruited to the peritoneal cavity by 24 hours after infection; this response can be replicated with intraperitoneal injection of thioredoxin peroxidase, an excretory/secretory (ES) product of F. hepatica. Furthermore, in vitro cultures of this parasite product with RAW 264.7 macrophages showed differentiation to an AAMΦ phenotype [7]. The importance of IL-4R signaling in AAMΦ development during helminth infection is underscored by studies of mice lacking IL-4Rα expression selectively in macrophages.…”

Fasciola hepatica tegumental antigens induce anergic‐like T cells via dendritic cells in a mannose receptor‐dependent manner

“…Similar to other helminths, infection generally leads to potent Th2/Tregulatory response with high levels of IL-5, IL-4, and IL-10 observed, while protective Th1 cytokines like IFN-γ are suppressed within hours post infection. Fasciola hepatica infection in mouse models resembles immune responses observed in the natural host with a decrease in protective Th1 immune responses and an increase in Th2/Treg-driven responses with enhanced numbers of M2-like macrophages, mast cells, and eosinophils [17][18][19].…”