Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.
<h4>Background</h4>TNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM de...
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2008
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oai:doaj.org-article:03a2d237b3284307b66e4c9f4bb6006d2021-11-25T06:11:43ZBoth functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.1932-620310.1371/journal.pone.0002608https://doaj.org/article/03a2d237b3284307b66e4c9f4bb6006d2008-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18612394/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>TNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.<h4>Methodology/principal findings</h4>LTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+) CD8(+) T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM.<h4>Conclusions/significance</h4>LTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.Dieudonnée TogbePaulo Loureiro de SousaMathilde FauconnierVictorine BoissayLizette FickStefanie ScheuKlaus PfefferRobert MenardGeorges E GrauBich-Thuy DoanJean Claude BeloeilLaurent ReniaAnna M HansenHelen J BallNicholas H HuntBernhard RyffelValerie F J QuesniauxPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 7, p e2608 (2008) |
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Medicine R Science Q Dieudonnée Togbe Paulo Loureiro de Sousa Mathilde Fauconnier Victorine Boissay Lizette Fick Stefanie Scheu Klaus Pfeffer Robert Menard Georges E Grau Bich-Thuy Doan Jean Claude Beloeil Laurent Renia Anna M Hansen Helen J Ball Nicholas H Hunt Bernhard Ryffel Valerie F J Quesniaux Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. |
| description |
<h4>Background</h4>TNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.<h4>Methodology/principal findings</h4>LTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+) CD8(+) T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM.<h4>Conclusions/significance</h4>LTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM. |
| format |
article |
| author |
Dieudonnée Togbe Paulo Loureiro de Sousa Mathilde Fauconnier Victorine Boissay Lizette Fick Stefanie Scheu Klaus Pfeffer Robert Menard Georges E Grau Bich-Thuy Doan Jean Claude Beloeil Laurent Renia Anna M Hansen Helen J Ball Nicholas H Hunt Bernhard Ryffel Valerie F J Quesniaux |
| author_facet |
Dieudonnée Togbe Paulo Loureiro de Sousa Mathilde Fauconnier Victorine Boissay Lizette Fick Stefanie Scheu Klaus Pfeffer Robert Menard Georges E Grau Bich-Thuy Doan Jean Claude Beloeil Laurent Renia Anna M Hansen Helen J Ball Nicholas H Hunt Bernhard Ryffel Valerie F J Quesniaux |
| author_sort |
Dieudonnée Togbe |
| title |
Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. |
| title_short |
Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. |
| title_full |
Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. |
| title_fullStr |
Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. |
| title_full_unstemmed |
Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. |
| title_sort |
both functional ltbeta receptor and tnf receptor 2 are required for the development of experimental cerebral malaria. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2008 |
| url |
https://doaj.org/article/03a2d237b3284307b66e4c9f4bb6006d |
| work_keys_str_mv |
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