Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety

BACKGROUND: Interleukin-6 (IL-6) is elevated in circulation with chronic stress and may contribute to neuro-behavioral complications. We have reported that repeated social defeat stress in mice caused recruitment of proinflammatory monocytes to the brain and triggered the onset of anxiety-like behavior. Therefore, the purpose of this study was to determine the role of IL-6 signaling in the peripheral immune response, neuroinflammation, and anxiety following stress. METHODS: Wild-type and IL-6 knockout mice were subjected to repeated social defeat, and immune and behavioral parameters were determined 14 hours later. RESULTS: Although monocyte release and recruitment to the brain during stress were maintained in the IL-6 knockout mice, anxiety and social avoidance were prevented. NanoString analysis of fluorescence-activated cell-sorted blood monocytes (CD11b(+)/Ly6C(hi)) and brain monocytes (CD11b(+) /CD45(hi)) revealed a unique pattern of immune-related gene expression that was dependent on stress and IL-6. For instance, blood monocytes after stress had a transcriptional signature and immune profile consistent with priming, which was attenuated in monocytes from IL-6 knockout stress mice. Moreover, the monocytes recruited to the brain and associated with the development of anxiety had a transcriptional signature (enhanced IL-1 beta, CD14, Mmp9, Myd88, Ager, and Stat3) that was dependent on IL-6. CONCLUSIONS: Here, we show the effects of IL-6 on the transcriptional signature of monocytes in circulation and brain after stress. Overall, robust increases in IL-6 after stress induced a primed profile in monocytes that were recruited to the brain and propagated IL-1-mediated inflammation and anxiety.