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2018 ; 9
(ä): 859
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Trypanosoma cruzi Exploits Wnt Signaling Pathway to Promote Its Intracellular
Replication in Macrophages
#MMPMID29743880
Volpini X
; Ambrosio LF
; Fozzatti L
; Insfran C
; Stempin CC
; Cervi L
; Motran CC
Front Immunol
2018[]; 9
(ä): 859
PMID29743880
show ga
During the acute phase of Trypanosoma cruzi infection, macrophages can act as
host cells for the parasites as well as effector cells in the early
anti-parasitic immune response. Thus, the targeting of specific signaling
pathways could modulate macrophages response to restrict parasite replication and
instruct an appropriate adaptive response. Recently, it has become evident that
Wnt signaling has immunomodulatory functions during inflammation and infection.
Here, we tested the hypothesis that during T. cruzi infection, the activation of
Wnt signaling pathway in macrophages plays a role in modulating the
inflammatory/tolerogenic response and therefore regulating the control of
parasite replication. In this report, we show that early after T. cruzi infection
of bone marrow-derived macrophages (BMM), ?-catenin was activated and Wnt3a,
Wnt5a, and some Frizzled receptors as well as Wnt/?-catenin pathway's target
genes were upregulated, with Wnt proteins signaling sustaining the activation of
Wnt/?-catenin pathway and then activating the Wnt/Ca(+2) pathway. Wnt signaling
pathway activation was critical to sustain the parasite's replication in BMM;
since the treatments with specific inhibitors of ?-catenin transcriptional
activation or Wnt proteins secretion limited the parasite replication.
Mechanistically, inhibition of Wnt signaling pathway armed BMM to fight against
T. cruzi by inducing the production of pro-inflammatory cytokines and indoleamine
2,3-dioxygenase activity and by downregulating arginase activity. Likewise, in
vivo pharmacological inhibition of the Wnts' interaction with its receptors
controlled the parasite replication and improved the survival of lethally
infected mice. It is well established that T. cruzi infection activates a
plethora of signaling pathways that ultimately regulate immune mediators to
determine the modulation of a defined set of effector functions in macrophages.
In this study, we have revealed a new signaling pathway that is activated by the
interaction between protozoan parasites and host innate immunity, establishing a
new conceptual framework for the development of new therapies.
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