Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation

TLDR

Inflammatory diseases outside the CNS trigger peripheral‑to‑brain communication that alters central neural activity and behavior. The study investigates monocyte infiltration into the brain during hepatic inflammation in mice and seeks to define the underlying mechanism. Using a mouse model of inflammatory liver injury, the authors showed that hepatic inflammation induces microglial production of MCP‑1/CCL2 via TNFα/TNFR1 signaling, which recruits circulating CCR2⁺ monocytes into the brain. They found that hepatic inflammation elevates cerebral MCP‑1/CCL2 and CCR2⁺ monocytes, that MCP‑1/CCL2 or CCR2 deficiency abolishes monocyte recruitment, that microglia produce MCP‑1/CCL2 before infiltration, and that TNFα/TNFR1 signaling is required for this pathway, revealing a novel peripheral‑to‑CNS communication route.

Abstract

In inflammatory diseases occurring outside the CNS, communication between the periphery and the brain via humoral and/or neural routes results in central neural changes and associated behavioral alterations. We have recently identified another immune-to-CNS communication pathway in the setting of organ-centered peripheral inflammation: namely, the entrance of immune cells into the brain. In our current study, using a mouse model of inflammatory liver injury, we have confirmed the significant infiltration of activated monocytes into the brain in mice with hepatic inflammation and have defined the mechanism that mediates this trafficking of monocytes. Specifically, we show that in the presence of hepatic inflammation, mice demonstrate elevated cerebral monocyte chemoattractant protein (MCP)-1 levels, as well as increased numbers of circulating CCR2-expressing monocytes. Cerebral recruitment of monocytes was abolished in inflamed mice that lacked MCP-1/CCL2 or CCR2. Furthermore, in mice with hepatic inflammation, microglia were activated and produced MCP-1/CCL2 before cerebral monocyte infiltration. Moreover, peripheral tumor necrosis factor (TNF)α signaling was required to stimulate microglia to produce MCP-1/CCL2. TNFα signaling via TNF receptor 1 (TNFR1) is required for these observed effects since in TNFR1 deficient mice with hepatic inflammation, microglial expression of MCP-1/CCL2 and cerebral monocyte recruitment were both markedly inhibited, whereas there was no inhibition in TNFR2 deficient mice. Our results identify the existence of a novel immune-to-CNS communication pathway occurring in the setting of peripheral organ-centered inflammation which may have specific implications for the development of alterations in cerebral neurotransmission commonly encountered in numerous inflammatory diseases occurring outside the CNS.