Growth Factor and Th2 Cytokine Signaling Pathways Converge at STAT6 to Promote Arginase Expression in Progressive Experimental Visceral Leishmaniasis

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.

Cross Talk between Histone Deacetylase 4 and STAT6 in the Transcriptional Regulation of Arginase 1 during Mouse Dendritic Cell Differentiation

“…Th2 cytokines are known to induce the expression of Arg1 in macrophages through JAK-mediated STAT6 phosphorylation (37,(45)(46)(47). The regulation of Arg1 in DCs is clearly distinct from that in macrophages.…”

Therapeutic effect of ursolic acid in experimental visceral leishmaniasis

“…On the contrary, IL-4 and IL-10 are recognized markers of susceptibility to infection (Osorio et al., 2014). In the present study, this dichotomy was evaluated by the relative expression levels of IFN-γ, IL-4, and IL-10 genes in the spleen.…”

“…This led to a strong expression of the gene encoding for L-arginase, an important enzyme that inhibits NO production (Osorio et al., 2014), which is essential for parasite elimination. Therefore, decreased expression of this cytokine following experimental treatments may be associated with a beneficial response against experimental VL.…”

Leishmania major Infection–Induced VEGF-A/VEGFR-2 Signaling Promotes Lymphangiogenesis That Controls Disease

“…Importantly, these pathways can induce angiogenesis in the absence of VEGFR-2 signaling (50-56). Therefore, we hypothesize that other angiogenic mediators, such as FGF-2 that is elevated during infection, may drive the expansion of the blood vasculature during leishmaniasis (57). Alternatively, these angiogenic factors may serve a redundant or compensatory role only upon the neutralization of VEGFR-2.…”