Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection

Abstract

Lipoproteins are able to neutralize bacterial lipopolysaccharide (LPS) and thereby inhibit the proinflammatory cytokine response. In a previous study, we demonstrated that hypercholesterolemic low density lipoprotein receptor knock-out (LDLr–/–) mice are protected against lethal endotoxemia and gram-negative infection. In the present study we investigated the susceptibility of apolipoprotein E knock-out mice (apoE–/–) to LPS and to Klebsiella pneumoniae. These mice have increased plasma lipoprotein concentrations in the very low density lipoprotein (VLDL)-sized fraction. Despite 8-fold higher plasma cholesterol levels compared to controls, and in contrast to LDLr–/– mice, apoE–/– mice were significantly more susceptible to endotoxemia and to K. pneumoniae infection. Circulating TNFα concentrations after intravenously injected LPS were 4- to 5-fold higher in apoE–/– mice, whereas IL-1α, IL-1β, and IL-6 did not differ. This TNF response was not due to an increased cytokine production capacity of cells from apoE–/– mice, as ex vivo cytokine production in response to LPS did not differ between apoE–/– and control mice. The LPS-neutralizing capacity of apoE–/– plasma was significantly less than that of controls. Most likely, the absence of apoE itself in the knock-out mice explains the failure to neutralize LPS, despite the very high cholesterol concentrations.—de Bont, N., M. G. Netea, P. N. M. Demacker, I. Verschueren, B. J. Kullberg, K. W. van Dijk, J. W. M. van der Meer, and A. F. H. Stalenhoef. Apolipoprotein E knockout-mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection. J. Lipid Res. 1999. 40: 680–685.

Keywords

• lipopolysaccharide
• tumor necrosis factor
• apolipoprotein E
• hypercholesterolemia
• neutralization