The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production.
Although activation of Toll-like receptor 4 (TLR4)-positive cells is essential for eliminating Gram-negative bacteria, overactivation of these cells by the TLR4 ligand LPS initiates a systemic inflammatory reaction and shock. Here we demonstrate that SPRET/Ei mice, derived from Mus spretus, exhibit a dominant resistance against LPS-induced lethality. This resistance is mediated by bone marrow-derived cells. Macrophages from these mice exhibit normal signaling and gene expression responses that depend on the myeloid differentiation factor 88 adaptor protein, but they are impaired in IFN-beta production. The defect appears to be specific for IFN-beta, although the SPRET/Ei IFN-beta promoter is normal. In vivo IFN-beta induction by LPS or influenza virus is very low in SPRET/Ei mice, but IFN-beta-treatment restores the sensitivity to LPS, and IFN type 1 receptor-deficient mice are also resistant to LPS. Because of the defective induction of IFN-beta, these mice are completely resistant to Listeria monocytogenes and highly sensitive to Leishmania major infection. Stimulation of SPRET/Ei macrophages leads to rapid down-regulation of IFN type 1 receptor mRNA expression, which is reflected in poor induction of IFN-beta-dependent genes. This finding indicates that the resistance of SPRET/Ei mice to LPS is due to disruption of a positive-feedback loop that amplifies IFN-beta production. In contrast to TLR4-deficient mice, SPRET/Ei mice resist both LPS and sepsis induced with Klebsiella pneumoniae.
Mahieu
Tina
T
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.
Park
Jin Mo
JM
Revets
Hilde
H
Pasche
Bastian
B
Lengeling
Andreas
A
Staelens
Jan
J
Wullaert
Andy
A
Vanlaere
Ineke
I
Hochepied
Tino
T
van Roy
Frans
F
Karin
Michael
M
Libert
Claude
C
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism; D004198:Disease Susceptibility; D015536:Down-Regulation; D025461:Feedback, Physiological; D005260:Female; D016899:Interferon-beta / Q000096:biosynthesis*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta