Euflammation dynamically regulates peripheral inflammation induced neuroimmune reactivity and sickness behavior

Abstract

Peripheral inflammation can trigger the production and release of inflammatory cytokines, leading to sickness behavior, fatigue, reduced cognitive function and other CNS responses. In the current study, we show that this immune to brain afferent signaling can be regulated by euflammation, which enhances the innate immune reactivity after the host has been challenged with increasing amounts of subthreshold levels of bacteria. When a sublethal dose of Escherichia coli was injected to the euflammatory animals inside euflammation induction locus (EIL) or outside EIL, global microglial activation, proinflammatory cytokine production in the brain, expression of endothelial cyclooxygenase II and induction of c-fos expression in the paraventricular nucleus of hypothalamus were all attenuated comparing to control mice receiving comparable injections. Euflammation also modulated innate immunity outside EIL by enhancing the bactericidal activity and upregulated inflammation-associated gene expression in spleen cells. When LPS was administered inside EIL, euflammatory mice showed reduced neuroimmune reactivity. In contrast, following intra air pouch (outside EIL) LPS injection, euflammatory mice exhibited exacerbated neuroinflammation and sickness behavior. Collectively, our study demonstrates that euflammation regulates innate immunity both inside and outside EIL. These adaptive immune alterations offer protection against bacteria infection but also engender vulnerability to endotoxin induced neuroinflammation.