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1.
PLoS One ; 12(6): e0179084, 2017.
Article in English | MEDLINE | ID: mdl-28591228

ABSTRACT

We evaluated the importance of neutrophils in the development of chronic lesions caused by L. Viannia spp. using the hamster as experimental model of American Cutaneous Leishmaniasis (ACL). Neutrophils infiltrated the lesion within the first six hours post-infection. Inhibition of this early infiltration using a polyclonal antibody or cyclophosphamide was associated with transient parasite control but the protective effect vanished when lesions became clinically apparent. At lesion onset (approximately 10 days p.i.), there was an increased proportion of both uninfected and infected macrophages, and subsequently a second wave of neutrophils infiltrated the lesion (after 19 days p.i.) This second neutrophil infiltration was associated with lesion necrosis and ulceration (R2 = 0.75) and maximum parasite burden. Intradermal delivery of N-formylmethionyl-leucyl-phenylalanine (fMLP), aimed to increase neutrophil infiltration, resulted in larger lesions with marked necrosis and higher parasite burden than in mock treated groups (p<0.001 each). In contrast, reduced neutrophil infiltration via cyclophosphamide-mediated depletion led to more benign lesions and lower parasite loads compared to controls (p<0.001 each). Neutrophils of the second wave expressed significantly lower GM-CSF, reactive oxygen species and nitric oxide than those of the first wave, suggesting that they had less efficient anti-leishmania activity. However, there was increased inflammatory cytokines and expression of neutrophil proteases (myeloperoxidase, cathepsin G and elastase) in lesions during the second wave of neutrophil infiltration compared with the levels reached during the first wave (6h p.i.). This suggests that augmented neutrophil proteases and inflammatory cytokines during the secondary wave of neutrophils could contribute to skin inflammation, ulceration and necrosis in ACL. The overall results indicate that neutrophils were unable to clear the infection in this model, and that the second wave of neutrophils played an important role in the severity of ACL.


Subject(s)
Inflammation/blood , Leishmaniasis, Cutaneous/blood , Necrosis/blood , Neutrophil Infiltration , Animals , Cricetinae , Disease Models, Animal , Female , Humans , Inflammation/parasitology , Inflammation/physiopathology , Leishmania/pathogenicity , Leishmaniasis, Cutaneous/parasitology , Leishmaniasis, Cutaneous/physiopathology , Macrophages/pathology , Necrosis/parasitology , Necrosis/physiopathology , Neutrophils/pathology , Nitric Oxide/metabolism , Parasite Load , Reactive Oxygen Species/metabolism , United States
2.
PLoS Pathog ; 10(6): e1004165, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24967908

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.


Subject(s)
Arginase/metabolism , Leishmaniasis, Visceral/immunology , Receptor, Fibroblast Growth Factor, Type 1/agonists , Receptor, IGF Type 1/agonists , STAT6 Transcription Factor/metabolism , Signal Transduction , Th2 Cells/immunology , Animals , Arginase/genetics , Cell Line , Cells, Cultured , Disease Progression , Enzyme Induction/drug effects , Host-Parasite Interactions/drug effects , Interleukin-4/metabolism , Leishmania donovani/growth & development , Leishmania donovani/immunology , Leishmania donovani/pathogenicity , Leishmania donovani/physiology , Leishmaniasis, Visceral/metabolism , Leishmaniasis, Visceral/parasitology , Leishmaniasis, Visceral/physiopathology , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Macrophages/parasitology , Mesocricetus , Protein Kinase Inhibitors/pharmacology , RNA Interference , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , STAT6 Transcription Factor/agonists , STAT6 Transcription Factor/antagonists & inhibitors , STAT6 Transcription Factor/genetics , Signal Transduction/drug effects , Th2 Cells/drug effects , Th2 Cells/metabolism , Th2 Cells/parasitology
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