Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Togbe
Dieudonnée
D
University of Orléans and CNRS, Molecular Immunology and Embryology UMR6218, Orleans, France.
de Sousa
Paulo Loureiro
PL
Fauconnier
Mathilde
M
Boissay
Victorine
V
Fick
Lizette
L
Scheu
Stefanie
S
Pfeffer
Klaus
K
Menard
Robert
R
Grau
Georges E
GE
Doan
Bich-Thuy
BT
Beloeil
Jean Claude
JC
Renia
Laurent
L
Hansen
Anna M
AM
Ball
Helen J
HJ
Hunt
Nicholas H
NH
Ryffel
Bernhard
B
Quesniaux
Valerie F J
VF
D000818:Animals; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D016779:Malaria, Cerebral / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010962:Plasmodium berghei / Q000472:pathogenicity; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D053259:Lymphotoxin beta Receptor; D047889:Receptors, Tumor Necrosis Factor, Type II