Abstract
BackgroundInnate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; however, whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities.MethodsThe experimental mice were pre-injected intraperitoneally with MPL before stress exposure. Depression was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify anxiety-like behaviors. Real-time polymerase chain reaction (PCR) and biochemical assays were employed to examine the gene and protein expression levels of pro-inflammatory markers.ResultsA single MPL injection at the dose of 400 and 800 μg/kg 1 day before stress exposure prevented CSDS-induced anxiety-like behaviors, and a single MPL injection (400 μg/kg) five but not 10 days before stress exposure produced similar effect. The preventive effect of MPL on anxiety-like behaviors was also observed in CSDS mice who received a second MPL injection 10 days after the first MPL injection or a 4 × MPL injection 10 days before stress exposure. MPL pre-injection also prevented the production of pro-inflammatory cytokines in the hippocampus and medial prefrontal cortex in CSDS mice, and inhibiting the central immune response by minocycline pretreatment abrogated the preventive effect of MPL on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine productions in the brain.ConclusionsPre-stimulation of the innate immune system by MPL can prevent chronic stress-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice.
Highlights
Innate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear
We found that pre-mobilization of the innate immune response by either single or repeated monophosphoryl lipid A (MPL) injections prevented chronic social defeat stress (CSDS)-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice, both of which were abrogated by innate immune inhibition
In the Elevated plus maze (EPM) test, we found that a single MPL injection 1 day before stress exposure at the dose of medial prefrontal cortex), IL-6 (B hippocampus; E medial prefrontal cortex), and TNF-α (C hippocampus; F cortex) in the hippocampus and medial prefrontal cortex (n = 10, **p < 0.01 vs. vehicle; #p < 0.05 or ##p < 0.01 vs. vehicle + CSDS)
Summary
Innate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities. Anxiety, which is defined as generalized anxiety disorder in human individuals, is a common psychological disorder in the modern society [1] It can induce a variety of social burdens which may increase the morbidity of the other psychological disorders, such as depression and post-traumatic stress disorders [2, 3]. The suppression of the over-production of pro-inflammatory cytokines in the brain could be potential strategy for the prevention of anxiety-associated behaviors
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