Patrolling monocytes sense peripheral infection and induce cytokine-mediated neuronal dysfunction

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Abstract

A new study reveals that virus-associated activation of a subset of circulating monocytes results in the release of the proinflammatory cytokine tumor necrosis factor (TNF)-α, which induces increased turnover of synapses in the brain and learning deficits in mice.

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Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

Thomas Blank, Claudia Detje, Alena Spiess … (2016)

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

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CX 3 CR1 + monocytes modulate learning and learning-dependent dendritic spine remodeling via TNFα

Juan Mauricio Garré, Hernandez Silva, Juan J. Lafaille … (2017)

Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms. Taken together, our results highlight CX3CR1high monocytes and TNF-α as potential therapeutic targets for preventing infection-induced cognitive dysfunction.

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Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation

Yochai Wolf, Anat Shemer, Michal Polonsky … (2017)

Using in vivo experimentation and an in vitro microfluidic system, Wolf et al. demonstrate that monocytes require low levels of self-made TNF for their survival, both during monopoiesis and under specific immune challenges. They highlight the significance of this autonomous mechanism in a mouse multiple sclerosis model in which TNF-deficient monocytes survive less in the inflamed spinal cord, resulting in delayed disease onset.

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Author and article information

Journal

Title: Nature Medicine

Abbreviated Title: Nat Med

Publisher: Springer Nature

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Created: June 6 2017

Publication date (Print): June 6 2017

Volume: 23

Issue: 6

Pages: 659-661

Article

DOI: 10.1038/nm.4349

PubMed ID: 28586340

SO-VID: b1d83e3c-85fb-4877-ae2c-a334dfc5b8d0

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Patrolling monocytes sense peripheral infection and induce cytokine-mediated neuronal dysfunction

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Neuronal Signaling

Most cited references 4

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

CX 3 CR1 + monocytes modulate learning and learning-dependent dendritic spine remodeling via TNFα

Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation

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