Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-γ-triggered JAK2 activation

Blanchette, Julie; Racette, Nathalie; Faure, Robert; Siminovitch, Katherine A.; Olivier, Martin

doi:10.1002/(sici)1521-4141(199911)29:11<3737::aid-immu3737>3.0.co;2-s

Cited by 153 publications

(149 citation statements)

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“…In addition, as our recent findings suggest, the capacity of Leishmania parasites to induce MU SHP-1 activity [6] is crucial for its survival within its host and to tame the early inflammatory response shown to be detrimental to the installation and progression of infection in SHP-1-deficient animals [18]. Thus, activation of MU PTP by Leishmania infection could represent a turning point in regulating chemokine expression levels.…”

Section: Expression Of Leukocyte Chemokine Receptors Inmentioning

confidence: 89%

“…Correspondence: Martin Olivier, McGill University, Department of Microbiology and Immunology, Duff Medical Building (Room 511), 3775 University Street, MontrØal (QuØbec), Canada H3A 2B4 Fax: +1-514-398-7052 e-mail: martin.olivier@mcgill.ca induced macrophage (MU) dysfunctions are related to the alteration of several phagocyte signaling events being dependent on Ca 2+ , protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and Janus kinase (JAK)2 [3][4][5][6][7][8][9]. The JAK2 phosphotyrosine-based signaling cascades seem to be particularly important because tyrosine phosphorylation has been shown to play a critical role in regulating many IFN-c-inducible MU functions that are inhibited by Leishmania infection (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…We and others have recently shown that Leishmania is capable of inducing MU protein tyrosine phosphatases (PTP) [6,9], leading to selective dephosphorylation of tyrosyl residues and inhibition of IFN-c-inducible JAK2 and MAPK signaling pathways [6,8,9]. In addition, using PTP inhibitors such as the peroxovanadium (pV) compound bpV(phen), we recently obtained evidence that PTP play a pivotal role in the installation and progression of Leishmania infection in vitro and in vivo [10].…”

Section: Introductionmentioning

confidence: 99%

“…In a subsequent study [11], we demonstrated that this pV-mediated protection against leishmaniasis was in part due to an increased production of nitric oxide and pro-inflammatory molecules (such as IL-6, IL-1b, MCP-1/CCL2 and MIP-2/CXCL1), accompanied by increased leukocyte recruitment. Furthermore, we showed that the PTP Src homology 2 domain phosphotyrosine phosphatase 1 (SHP-1), recognized as a negative regulator of numerous phosphotyrosine-dependent signaling pathways in hematopoietic cells [12][13][14][15][16][17], is specifically induced by Leishmania infection and involved in the deactivation of the IFN-c-induced JAK2-dependent signaling pathway [6].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

et al. 2005

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Modulation of the phagocyte protein tyrosine phosphatase (PTP) SHP-1 by the parasite Leishmania favors its survival and propagation within its mammalian host. In vivo, the absence of SHP-1 leads to virtually absent footpad swelling, accompanied by enhanced inducible nitric oxide synthase expression. In this study, using an air pouch model, we show that viable motheaten SHP-1-deficient mice harbored a stronger inflammatory response against Leishmania infection than wild-type mice. This response was portrayed by higher pro-inflammatory cytokine (TNF-a, IL-1b and IL-6) expression and secretion and by greater chemokine and chemokine receptor expression. These inflammatory molecules were probably responsible for the stronger cellular recruitment, mainly of neutrophils, seen at the site of infection in viable motheaten mice within 6 h post inoculation. We also provide strong evidence that protein tyrosine phosphatases in general, and SHP-1 in particular, are important regulators of chemokine gene expression. Overall, this study suggests that the ability of Leishmania to induce SHP-1 activity in its host allows the taming of an otherwise strong innate inflammatory response that would be detrimental for its survival and progression.

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Section: Expression Of Leukocyte Chemokine Receptors Inmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

et al. 2005

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“…IFN-γ signals through the JAK/STAT pathway and is critical for the induction of nitric oxide, but this pathway is suppressed by Leishmania (Nandan & Reiner, 1995). Interaction of Leishmania promastigotes with macrophages activates SHP-1 which shows a strong and increased interaction with JAK2 resulting in its deactivation (Blanchette, Racette, Faure, Siminovitch, & Olivier, 1999). Further studies show that JAK2 inactivation by SHP-1 results in diminished nitric oxide production which favors parasite survival (Blanchette, Abu-Dayyeh, Hassani, Whitcombe, & Olivier, 2009).…”

Section: Mechanisms Of Immune Evasionmentioning

confidence: 99%

Mechanisms of Immune Evasion in Leishmaniasis

Gupta

Oghumu

Satoskar

2013

Advances in Applied Microbiology

212

156

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Diseases caused by Leishmania present a worldwide problem, and current therapeutic approaches are unable to achieve a sterile cure. Leishmania is able to persist in host cells by evading or exploiting host immune mechanisms. A thorough understanding of these mechanisms could lead to better strategies for effective management of Leishmania infections. Current research has focused on parasite modification of host cell signaling pathways, entry into phagocytic cells, and modulation of cytokine and chemokine profiles that alter immune cell activation and trafficking to sites of infection. Immuno-therapeutic approaches that target these mechanisms of immune evasion by Leishmania offer promising areas for preclinical and clinical research.

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Leishmania donovani promastigotes evade the activation of mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase-1/2 during infection of naive macrophages

Privé¹,

Descoteaux²

2000

Eur. J. Immunol.

135

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The protozoan parasite Leishmania fails to activate naive macrophages for proinflammatory cytokines production, and selectively impairs signal transduction pathways in infected macrophages. Because mitogen‐activated protein kinases (MAPK)‐ and NF‐κB‐dependent signaling pathways regulate proinflammatory cytokines release, we investigated their activation in mouse bone marrow‐derived macrophages (BMM) exposed to Leishmania donovani promastigotes. In naive BMM, the parasite failed to induce the phosphorylation of p38 MAPK, c‐Jun N‐terminal kinase (JNK), and extracellular signal‐regulated kinase (ERK)1/2, as well as the degradation of IκB‐α. The use of L. donovani mutants defective in the biosynthesis of lipophosphoglycan revealed that evasion of ERK1/2 activation requires surface expression of the repeating unit moiety of this virulence determinant. In IFN‐γ‐primed BMM, L. donovani promastigotes strongly induced the phosphorylation of p38 MAPK and ERK1/2, and the use of selective inhibitors for ERK (PD98059) and p38 MAPK (SB203580) revealed that both kinases are required for L. donovani‐induced TNF‐α but not NO2– release. Collectively, these data suggest that both p38 MAPK and ERK1/2 pathways participate in some Leishmania‐induced responses in IFN‐γ‐primed BMM. The ability of L. donovani promastigotes to avoid MAPK and NF‐κB activation in naive macrophages may be part of the strategy evolved by this parasite to evade innate immune responses.

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Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-γ-triggered JAK2 activation

Cited by 153 publications

References 40 publications

Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

Mechanisms of Immune Evasion in Leishmaniasis

Leishmania donovani promastigotes evade the activation of mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase-1/2 during infection of naive macrophages

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