The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-β production

Although activation of TLR4-positive cells is essential for eliminating Gram-negative bacteria, over-activation of these cells by the TLR4 ligand lipopolysaccharide (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 have normal MyD88-dependent responses, but they are impaired for Interferon-β (IFN-β) production and downstream signaling. IRF-3 phosphorylation and gene induction are normal. The defect appears to be specific for IFN-β, although the SPRET/Ei IFN-β promoter is normal. In vivo IFN-β induction by LPS or influenza virus are very low in SPRET/Ei, IFN-β-treatment restores the sensitivity to LPS and IFNAR1-/mice indeed also resist LPS. Due to the defective induction of IFN-β, these mice are completely resistant to Listeria monocytogenes and highly sensitive to Leishmania major infection. Stimulation of SPRET/Ei macrophages leads to rapid downregulation of the IFNAR1 mRNA expression, which is reflected in poor induction of IFN-β-dependent genes. This indicates that the resistance of SPRET/Ei to LPS is due to disruption of the positive-feedback loop for amplifying IFN-β production. In contrast to TLR4-deficient mice, SPRET/Ei mice resist both LPS and sepsis induced with Klebsiella pneumoniae.