Growth factor and Th2 cytokine signaling pathways converge at STAT6 to promote arginase expression in progressive experimental visceral leishmaniasis.

Vern B Carruthers,E Yaneth Osorio,Audrie A Medina,Omar A Saldarriaga,Alda M Da Cruz,Peter C Melby,Bruno L Travi

doi:10.1371/journal.ppat.1004165

Vern B Carruthers, E Yaneth Osorio + Show 5 more

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https://doi.org/10.1371/journal.ppat.1004165

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Abstract

Host arginase 1 (arg1) expression is a significant contributor to the pathogenesis of progressive visceral leishmaniasis (VL), a neglected tropical disease caused by the intracellular protozoan Leishmania donovani. Previously we found that parasite-induced arg1 expression in macrophages was dependent on STAT6 activation. Arg1 expression was amplified by, but did not require, IL-4, and required de novo synthesis of unknown protein(s). To further explore the mechanisms involved in arg1 regulation in VL, we screened a panel of kinase inhibitors and found that inhibitors of growth factor signaling reduced arg1 expression in splenic macrophages from hamsters with VL. Analysis of growth factors and their signaling pathways revealed that the Fibroblast Growth Factor Receptor 1 (FGFR-1) and Insulin-like Growth Factor 1 Receptor (IGF-1R) and a number of downstream signaling proteins were activated in splenic macrophages isolated from hamsters infected with L. donovani. Recombinant FGF-2 and IGF-1 increased the expression of arg1 in L. donovani infected hamster macrophages, and this induction was augmented by IL-4. Inhibition of FGFR-1 and IGF-1R decreased arg1 expression and restricted L. donovani replication in both in vitro and ex vivo models of infection. Inhibition of the downstream signaling molecules JAK and AKT also reduced the expression of arg1 in infected macrophages. STAT6 was activated in infected macrophages exposed to either FGF-2 or IGF-1, and STAT6 was critical to the FGFR-1- and IGF-1R-mediated expression of arg1. The converse was also true as inhibition of FGFR-1 and IGF-1R reduced the activation of STAT6 in infected macrophages. Collectively, these data indicate that the FGFR/IGF-1R and IL-4 signaling pathways converge at STAT6 to promote pathologic arg1 expression and intracellular parasite survival in VL. Targeted interruption of these pathological processes offers an approach to restrain this relentlessly progressive disease.

Highlights

Visceral leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani or L. infantum, is one of the ‘‘Neglected Tropical Diseases’’ that impacts the poor of the world
Visceral leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani, is a progressive infection that is common in impoverished populations of the world
We found that host macrophages infected with Leishmania donovani are activated in a way that leads to the expression of arginase, an enzyme that counteracts the cell’s mechanisms that control the infection

Summary

Introduction

Visceral leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani or L. infantum, is one of the ‘‘Neglected Tropical Diseases’’ that impacts the poor of the world. Active VL is characterized by a relentlessly progressive infection with cachexia, massive splenomegaly, pancytopenia and death. Macrophages, the primary target of intracellular Leishmania infection, may take on distinct phenotypes in response to parasite signals and inflammatory stimuli within the infected microenvironment. Activated (M1) macrophages respond to IFN-c and microbial products by generating antimicrobial molecules that effectively kill Leishmania and other intracellular pathogens [3,4]. Central to the killing of intracellular parasites is the production of nitric oxide by the action of inducible nitric oxide synthase 2 (NOS2) on the substrate L-arginine. Alternatively activated or M2 macrophages, which are typically generated by exposure to type 2 cytokines (IL-4, IL-13), fail to produce antimicrobial effector molecules to kill intracellular pathogens and serve to dampen inflammation and promote wound healing [5,6]

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