Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Fauconnier, Mathilde; Bourigault, Marie-Laure; Même, Sandra; Szeremeta, Frédéric; Palomo, Jennifer; Danneels, Adeline; Charron, Sabine; Fick, Lizette; Jacobs, Muazzam; Belœil, Jean‐Claude; Ryffel, Bernhard; Quesniaux, Valérie

doi:10.1016/j.ajpath.2010.11.008

Cited by 25 publications

(33 citation statements)

References 41 publications

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“…Therefore, disruption of IL-12Rb2, while protecting from ECM development, had no strong effect on the typical hematological responses to PbA infection in mice, with the notable exception of the lymphocyte counts, which were decreased less than those in WT mice on day 7 postinfection. Furthermore, strong lymphocytosis was evident 2-3 wk postinfection in IL-12Rb2-deficient mice, as observed previously in ECM-resistant, protein kinase C-u-deficient mice (10). The propagation of PbA infection in erythrocytes was totally IL-12Rb2 independent, because the mice succumbed within 3 wk of severe parasitemia and anemia.…”

Section: Discussionsupporting

confidence: 57%

“…In vivo analyses showed no brain sequestration of mononuclear cells, no vascular leak, no hemorrhage, and no inflammation in the absence of IL-12Rb2, which were evident in PbA-infected WT mice. In contrast, the absence of IL-12Rb2 did not affect PbA-induced pulmonary microvascular damage, thus confirming the different pathophysiology of PbA-induced ECM and lung pathology (10,38,39). Thus, we demonstrated that PbA-induced brain microvascular damage and inflammation are mainly IL-12Rb2 dependent, whereas PbAinduced lung microvascular damage, edema, and alveolitis are IL-12Rb2 independent.…”

Section: Discussionmentioning

confidence: 46%

“…Histological analysis and immunohistological staining were performed as described (10). Mice were euthanized and perfused with intracardiac sterile PBS/0.002 M EDTA to remove circulating RBCs and leukocytes from the brain and lungs.…”

Section: Histology and Immunohistological Stainingmentioning

confidence: 99%

“…For each sample, 5000 cells from the mononuclear population (gated on the CD3 + cell population) were scored. Data were analyzed using a BD Canto II flow cytometer and FlowJo software (10).…”

Section: Immunophenotyping Of Brain-sequestered Leukocytesmentioning

confidence: 99%

“…Indeed, CD8 + T cells are the primary effector cells of ECM in the PbA mouse model, although their precise mechanism of action remains unresolved (3). We reported recently that the absence of protein kinase C-u expression, a critical regulator of TCR signaling and T cell activation, prevents ECM pathogenesis upon PbA infection (10).…”

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confidence: 99%

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IL-12Rβ2 Is Essential for the Development of Experimental Cerebral Malaria

Fauconnier

Palomo

Bourigault

et al. 2012

The Journal of Immunology

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A Th1 response is required for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The role of pro-Th1 IL-12 in malaria is complex and controversial. In this study, we addressed the role of IL-12Rβ2 in ECM development. C57BL/6 mice deficient for IL-12Rβ2, IL-12p40, or IL-12p35 were analyzed for ECM development after blood-stage PbA infection in terms of ischemia and blood flow by noninvasive magnetic resonance imaging and angiography, T cell recruitment, and gene expression. Without IL-12Rβ2, no neurologic sign of ECM developed upon PbA infection. Although wild-type mice developed distinct brain microvascular pathology, ECM-resistant, IL-12Rβ2–deficient mice showed unaltered cerebral microcirculation and the absence of ischemia after PbA infection. In contrast, mice deficient for IL-12p40 or IL-12p35 were sensitive to ECM development. The resistance of IL-12Rβ2–deficient mice to ECM correlated with reduced recruitment of activated T cells and impaired overexpression of lymphotoxin-α, TNF-α, and IFN-γ in the brain after PbA infection. Therefore, IL-12Rβ2 signaling is essential for ECM development but independent from IL-12p40 and IL-12p35. We document a novel link between IL-12Rβ2 and lymphotoxin-α, TNF-α, and IFN-γ expression, key cytokines for ECM pathogenesis.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 46%

Section: Histology and Immunohistological Stainingmentioning

confidence: 99%

Section: Immunophenotyping Of Brain-sequestered Leukocytesmentioning

confidence: 99%

mentioning

confidence: 99%

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IL-12Rβ2 Is Essential for the Development of Experimental Cerebral Malaria

Fauconnier

Palomo

Bourigault

et al. 2012

The Journal of Immunology

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Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood‐stage Plasmodium bergheiANKA

et al. 2013

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Cerebral malaria is a severe complication ofEur. J. Immunol. 2013Immunol. . 43: 2683Immunol. -2695 Plasmodium falciparum-infected children and young adults [1]. Cerebral malaria pathophysiology is still poorly understood, combining cerebral vascular obstruction, and exacerbated immune responses. Indeed, investigations in humans and mice documented the sequestration of erythrocytes, parasitized or not, platelets and leucocytes in cerebral blood vessels with an increased proinflammatory cytokine expression [1][2][3]. The specific role of T cells in cerebral malaria pathogenesis has been difficult to address in humans. In mice however, T-cell sequestration and activation in the brain are crucial steps for experimental cerebral malaria (ECM) development after Plasmodium berghei ANKA (PbA) infection [4][5][6][7]. In particular, αβ-CD8 + T cells sequestrated in the brain play a pathogenic, effector role for ECM development [6], and we showed recently a role for protein kinase C-θ (PKC-θ) in PbAinduced ECM pathogenesis [8]. Besides being a critical regulator of TCR signaling and T-cell activation, PKC-θ is involved in interferon type I/II signaling in human T cells [9]. Type II IFN-γ is essential for PbA-induced ECM development [10][11][12], promoting CD8 + T-cell accumulation in the brain [7,[12][13][14]. Type IIFNs are induced during viral infection but they also contribute to the antibacterial immune response. ResultsThe IFN-γ pathway is essential for ECM development upon sporozoite PbA infectionThe IFN-γ pathway is central for ECM development after bloodstage PbA infection. We first assessed the role of this pathway in preerythrocytic/intrahepatic stage infection by investigating ECM neurological signs development in IFN-γR1 −/− mice. Following the injection of 1000 sporozoites, 60% of the WT control mice developed typical ECM neurological symptoms, such as ataxia, loss of grip strength, progressive paralysis, and coma, and succumbed within 8-9 days, as previously described [22]. In contrast, IFN-γR1 −/− mice were fully resistant to the same challenge, surviving 30 days with no ECM neurological signs (Fig. 1A). Therefore, type II IFN-γ pathway is essential for ECM development after PbA sporozoite infection.Hampered ECM development in the absence of IFN-α/β pathway upon hepatic or blood-stage PbA infectionThe role of type I IFN-α/β versus type II IFN-γ pathways in ECM development after infection with hepatic or blood-stage PbA was then assessed in mice deficient for either IFNAR1 or IFN-γR1. IFNAR1 −/− mice were partially protected against ECM following sporozoite-initiated infection, only 20% dying before day 10, and 40% eventually developing typical ECM neurological symptoms, which reflected a delayed ECM development after infection with sporozoites ( Fig. 1A), as compared with WT control mice, 60% of which developed ECM and died before day 10, and IFN-γR1-deficient mice, which were fully resistant to PbA challenge. After injection of PbA-parasited red blood cells (10 5 pRBC/ mouse), WT mice succumbed within 7-...

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Stable tumor vessel normalization with pO2 increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment

et al. 2013

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Tumor hypoxia is a characteristic of cancer cell growth and invasion, promoting angiogenesis, which facilitates metastasis. Oxygen delivery remains impaired because tumor vessels are anarchic and leaky, contributing to tumor cell dissemination. Counteracting hypoxia by normalizing tumor vessels in order to improve drug and radio therapy efficacy and avoid cancer stem-like cell selection is a highly challenging issue. We show here that inositol trispyrophosphate (ITPP) treatment stably increases oxygen tension and blood flow in melanoma and breast cancer syngeneic models. It suppresses hypoxia-inducible factors (HIFs) and proangiogenic/glycolysis genes and proteins cascade. It selectively activates the tumor suppressor phosphatase and tensin homolog (PTEN) in vitro and in vivo at the endothelial cell (EC) level thus inhibiting PI3K and reducing tumor AKT phosphorylation. These mechanisms normalize tumor vessels by EC reorganization, maturation, pericytes attraction, and lowering progenitor cells recruitment in the tumor. It strongly reduces vascular leakage, tumor growth, drug resistance, and metastasis. ITPP treatment avoids cancer stem-like cell selection, multidrug resistance (MDR) activation and efficiently enhances chemotherapeutic drugs activity. These data show that counteracting tumor hypoxia by stably restoring healthy vasculature is achieved by ITPP treatment, which opens new therapeutic options overcoming hypoxia-related limitations of antiangiogenesis-restricted therapies. By achieving long-term vessels normalization, ITPP should provide the adjuvant treatment required in order to overcome the subtle definition of therapeutic windows for in vivo treatments aimed by the current strategies against angiogenesis-dependent tumors.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-013-0992-6) contains supplementary material, which is available to authorized users.

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Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Cited by 25 publications

References 41 publications

IL-12Rβ2 Is Essential for the Development of Experimental Cerebral Malaria

IL-12Rβ2 Is Essential for the Development of Experimental Cerebral Malaria

Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood‐stage Plasmodium bergheiANKA

Stable tumor vessel normalization with pO2 increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment

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