C3H/HeJ mice are refractory to lipopolysaccharide in the brain

C3H/HeJ mice are refractory to lipolysaccharide (LPS) in the periphery, primarily because their macrophages do not respond to LPS and produce pro-inflammatory cytokines such as interleukin-1 (IL-1). To determine if they are also refractory to LPS in the brain, behavior of C3H/HeJ mice was compared to LPS-sensitive C3H/HeOuJ mice following intracerebroventricular (ICV) injection of LPS. Whereas ICV injection of LPS (3-1000 ng/mouse) depressed social behavior, food motivation, object investigation and body weight in C3H/HeOuJ mice, C3H/HeJ mice were entirely refractory to LPS in the brain. To determine if the refractoriness of C3H/HeJ mice could result from an inability to synthesize IL-1, recombinant murine IL-1 was injected ICV in both mouse strains. Central administration of IL-1 (1 or 2 ng/mouse) depressed social behavior and body weight similarly in both endotoxin-sensitive C3H/HeOuJ mice and endotoxin-resistant C3H/HeJ mice. That C3H/HeJ mice were refractory to the behavioral effects of central LPS, but not IL-1, suggests that microglia (and other cells in the brain) in C3H/HeJ mice have in common with peripheral macrophages, an inability to respond to LPS and produce cytokines. These data suggest a genetic basis for sickness behavior and demonstrate the utility of preventing central cytokine production in manipulating LPS-induced sickness behavior.