Insulin-Like Growth Factor-I Induces Arginase Activity in<i>Leishmania amazonensis</i>Amastigote-Infected Macrophages through a Cytokine-Independent Mechanism

Vendrame, Célia Maria Vieira; Carvalho, Matheus Furtado de; Tempone, André G.; Goto, Hiro

doi:10.1155/2014/475919

Cited by 9 publications

(11 citation statements)

References 53 publications

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“…The expression of arginase-1 is increased, while NO synthesis is inhibited by catecholamines, making it likely that they promote M2 activation [ 125 , 126 ]. M2 macrophages also produce insulin-like growth factor-1 (IGF-1) [ 106 , 127 , 128 ], which can help tissue regeneration [ 127 ] and have a role in sustaining M2 activation [ 129 ]. Adiponectin gene expression has been shown in mouse adipose tissue macrophages, and its transcript level is diminished when M2 activation is compromised [ 122 ].…”

Section: Overview Of the M2 Macrophage Markersmentioning

confidence: 99%

Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

Röszer

2015

Mediators of Inflammation

1,392

1,125

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The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed.

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Section: Overview Of the M2 Macrophage Markersmentioning

confidence: 99%

Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

Röszer

2015

Mediators of Inflammation

1,392

1,125

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“…At 6 hours post-infection, we could detect an 8-fold increase of parasite transcripts in those ears co-injected with PSG, translating to a 4.3-fold increase in parasite burden ( Fig 4A ). From our Affymetrix and RTqPCR results of PSG inoculated into skin we found that PSG significantly increased the early expression of IL-10 and IGF1 (9 and 4-fold change respectively), both known inducers of arginase activity in macrophages [ 59 , 60 ]. This was confirmed in vitro when unstimulated bone-marrow macrophages (BMMΦ) were co-incubated with increasing amounts of PSG, IL-10 or IGF1 for 48 hours ( Fig 4B ).…”

Section: Resultsmentioning

confidence: 99%

Leishmania proteophosphoglycans regurgitated from infected sand flies accelerate dermal wound repair and exacerbate leishmaniasis via insulin-like growth factor 1-dependent signalling

et al. 2018

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Leishmania parasites are transmitted to vertebrate hosts by female phlebotomine sand flies as they bloodfeed by lacerating the upper capillaries of the dermis with their barbed mouthparts. In the sand fly midgut secreted proteophosphoglycans from Leishmania form a biological plug known as the promastigote secretory gel (PSG), which blocks the gut and facilitates the regurgitation of infective parasites. The interaction between the wound created by the sand fly bite and PSG is not known. Here we nanoinjected a sand fly egested dose of PSG into BALB/c mouse skin that lead to the differential expression of 7,907 transcripts. These transcripts were transiently up-regulated during the first 6 hours post-wound and enriched for pathways involved in inflammation, cell proliferation, fibrosis, epithelial cell differentiation and wound remodelling. We found that PSG significantly accelerated wound healing in vitro and in mice; which was associated with an early up-regulation of transcripts involved in inflammation (IL-1β, IL-6, IL-10, TNFα) and inflammatory cell recruitment (CCL2, CCL3, CCL4, CXCL2), followed 6 days later by enhanced expression of transcripts associated with epithelial cell proliferation, fibroplasia and fibrosis (FGFR2, EGF, EGFR, IGF1). Dermal expression of IGF1 was enhanced following an infected sand fly bite and was acutely responsive to the deposition of PSG but not the inoculation of parasites or sand fly saliva. Antibody blockade of IGF1 ablated the gel’s ability to promote wound closure in mouse ears and significantly reduced the virulence of Leishmania mexicana infection delivered by an individual sand fly bite. Dermal macrophages recruited to air-pouches on the backs of mice revealed that IGF1 was pivotal to the PSG’s ability to promote macrophage alternative activation and Leishmania infection. Our data demonstrate that through the regurgitation of PSG Leishmania exploit the wound healing response of the host to the vector bite by promoting the action of IGF1 to drive the alternative activation of macrophages.

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“…Based on our previous experimental data, IGF-I can play a role in the progression of Leishmania ( Leishmania ) amazonensis infection by (i) decreasing NO production in macrophages and allowing parasite multiplication, (ii) modulating immune responses by increasing TGF-β and decreasing IFNγ production in promastigote infected macrophages, and (iii) inducing apoptotic mimicry characterized by exposure of phosphatidyl serine on amastigotes but without leading to death [ 15 , 16 ]. However, it is unknown whether similar effects of IGF-I would occur in other Leishmania species.…”

Section: Discussionmentioning

confidence: 99%

“…braziliensis [ 1 ] and different biological effects may occur upon IGF-I stimulus, we initially studied its effect on promastigotes. Focusing on the increase of arginase activity of the parasite, which was seen as main effect of IGF-I [ 16 ], we confronted more complex outcomes that were dependent on Leishmania isolates, whether coming from patients with CL, ML or DL. IGF-I induced higher basal arginase activity in L .…”

Section: Discussionmentioning

confidence: 99%

“…amazonensis showed effects increasing the parasite growth and cutaneous leishmaniasis lesion development [ 11 ]. In Leishmania -macrophage interaction, IGF-I exerts effect on Leishmania and host cells, mainly inducing arginase expression and activity, leading to alternative activation of the macrophages interfering with inducible nitric oxide synthase expression [ 11 , 15 , 16 ]. Because biological effects may differ in other species and American tegumentary leishmaniasis is mostly caused by L .…”

Section: Introductionmentioning

confidence: 99%

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Insulin-like growth factor-I serum levels and their biological effects on Leishmania isolates from different clinical forms of American tegumentary leishmaniasis

et al. 2016

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AbstractsBackgroundAmerican tegumentary leishmaniasis (ATL) in Brazil is mostly caused by Leishmania (Viannia) braziliensis, with known forms of the disease being cutaneous (CL), mucosal (ML) and disseminated (DL) leishmaniasis. The development of the lesion in ATL is related both to the persistence of the Leishmania in the skin and to the parasite-triggered immune and inflammatory responses that ensue lesions. In this context one factor with expected role in the pathogenesis is insulin-like growth factor (IGF)-I with known effects on parasite growth and healing and inflammatory processes. In the present study, we addressed the effect of IGF-I on intracellular amastigote isolates from CL, ML and DL patients within human macrophage and we evaluated the IGF-I and IGF-binding protein-3 (IGFBP3) serum levels in patients presenting different clinical forms and controls from the endemic area.MethodsWe evaluated biological variability in the responses of intracellular amastigotes of Leishmania isolates derived from CL, ML, and DL patients from an area for ATL in response to IGF-I. Intracellular amastigote growth was evaluated using the human macrophage cell line THP-1. Arginase activity in infected cells was evaluated quantifying the generated urea concentration. Serum samples from patients and controls were assayed using chemiluminescent immunometric assay to determine IGF-I and IGFBP3 levels.ResultsWe observed an increase in intracellular parasitism upon IGF-I stimulus in 62.5 % of isolates from CL, in 85.7 % from ML and only 42.8 % from DL cases. In DL, the basal arginase activity was lower than that of CL. We then evaluated the IGF-I and IGFBP3 serum levels in patients, and we observed significantly lower levels in ML and DL than in CL and control samples.ConclusionsThe data suggest that IGF-I is modulated distinctly in different clinical forms of tegumentary leishmaniasis. IGF-I seemingly exerts effect on parasite growth likely contributing to its persistence in the skin in earlier phase. In addition the decreased IGF-I serum levels may affect the modulation of inflammation and lesion healing in chronic phase. In view of potential role of IGF-I in the pathogenesis of ATL we can speculate on therapeutic procedures taking into account the local IGF-I level.

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Insulin-Like Growth Factor-I Induces Arginase Activity inLeishmania amazonensisAmastigote-Infected Macrophages through a Cytokine-Independent Mechanism

Cited by 9 publications

References 53 publications

Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

Leishmania proteophosphoglycans regurgitated from infected sand flies accelerate dermal wound repair and exacerbate leishmaniasis via insulin-like growth factor 1-dependent signalling

Insulin-like growth factor-I serum levels and their biological effects on Leishmania isolates from different clinical forms of American tegumentary leishmaniasis

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