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

By C. D’Mello, T. Le, M. Swain. Journal of Neuroscience, 2009

658 citations recorded by the source corpus.

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.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/ab385a02fcf1ec6108279eb8b4ddff86a4fb2fdc

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Citations in the corpus

Cytokine Targets in the Brain: Impact on Neurotransmitters and Neurocircuits (2013, result): “These pathways include (1) “humoral” routes that involve passage of circulating cytokines through leaky regions in the blood brain barrier such as the circumventricular organs and active transport of circulating cytokines into brain parenchyma via cytokine specific saturable transporters,[40] (2) a ”
Immune System to Brain Signaling: Neuropsychopharmacological Implications (2011, background): “…4) transmission of cytokine signals via afferent nerve fibers, such as the vagus nerve, and 5) entry into the brain parenchyma of peripherally activated monocytes (Watkins et al., 1995;Plotkin et al., 1996;Rivest et al., 2000;Konsman et al., 2002;Quan and Banks, 2007;D’Mello et al., 2009).”
Microglia: biology and pathology (2009, background): “Microglia recruit monocytes into the brain during peripheral organ inflammation [38].”
Immune activation in brain aging and neurodegeneration: too much or too little? (2009, result): “In support of this concept, recent studies in a model of liver injury and peripheral inflammation suggested that fluorescently tagged monocytes can infiltrate the brain in a chemokine receptor CCR2-dependent manner (D’Mello et al., 2009).”
Gut feelings: the emerging biology of gut–brain communication (2011, background): “Additional non-vagal mechanisms by which peripheral cytokines can reach the CNS have been reporte”
Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications (2013, background): “…et al., 1997, Miller, 1999, Matsumura and Kobayashi, 2004), and 5.) activated immune cells such as monocytes/macrophages and T cells can be recruited from the periphery to the brain parenchyma, and these cells can in turn produce cytokines in the brain (Shaftel et al., 2007, D'Mello et al., 2009).”