title: IL-12Rβ2 is essential for the development of experimental cerebral malaria.
abstract: 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.
authors.affiliation: Immunologie et Embryologie Moléculaires, Centre National de la Recherche Scientifique, 45071 Orléans, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Fauconnier
authors.forename: Jennifer
authors.initials: J
authors.lastname: Palomo
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Bourigault
authors.forename: Sandra
authors.initials: S
authors.lastname: Meme
authors.forename: Frédéric
authors.initials: F
authors.lastname: Szeremeta
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beloeil
authors.forename: Adeline
authors.initials: A
authors.lastname: Danneels
authors.forename: Sabine
authors.initials: S
authors.lastname: Charron
authors.forename: Pascal
authors.initials: P
authors.lastname: Rihet
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Valérie F J
authors.initials: VF
authors.lastname: Quesniaux
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000096:biosynthesis; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053712:Interleukin-12 Receptor beta 2 Subunit; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma