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

Lipoproteins are able to neutralize bacterial lipopolysaccharide (LPS) and thereby inhibit the proinflammatory cytokine response. In a previous study, we demonstrated that hypercholesterolemic lour density lipoprotein recepto r knock-out (LDLr-/-) mice are protected against lethal endotoxemia and gra m-negative infection, In the present study we investigated the susceptibili ty of apolipoprotein E knock-out mice (apoE-/-) to LPS and to Klebsiella pn eumoniae. These mice have increased plasma lipoprotein concentrations in th e 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 TNF alpha concentrations after intr avenously injected LPS were 4- to 5-fold higher in apoE-/- mice, whereas IL -1 alpha, IL-1 beta, and IL-6 did not differ. This TNF response was not due to an increased cytokine production capacity of cells from apoE-/- mice, a s ex vivo cytokine production in response to LPS did not differ between apo E-/- 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, despit e the very high cholesterol concentrations.