A microglia-cytokine axis to modulate synaptic connectivity and function

Werneburg, Sebastian; Feinberg, Philip A; Johnson, Kasey M.; Schafer, Dorothy P.

doi:10.1016/j.conb.2017.10.002

Cited by 97 publications

(64 citation statements)

References 65 publications

(64 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Microglia constantly survey their local environment and respond to extracellular cues (e.g., ATP) to maintain homeostasis [2,3] . Other specific physiological functions of microglia include removal of dead neurons and cellular debris [2,3] , synaptic pruning [4] , and regulation of synaptic connectivity and plasticity [5][6][7] . Microglia are also integral to innate immunity and are instrumental in neuroinflammation [8,9] .…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1β-induced inflammatory signaling in C20 human microglial cells

Davis¹,

Buck²,

McCracken³

et al. 2018

View full text Add to dashboard Cite

Increased inflammatory signaling in microglia is implicated in the pathogenesis of neurodegenerative diseases, trauma, psychiatric disorders, and anxiety/depression. Understanding inflammatory signaling in microglia is critical for advancing treatment options. Studying rodent-derived microglia has yielded substantial information, yet, much remains to better understand inflammatory signaling in human microglia. Hence, there is great interest in developing immortalized human microglial cell lines. The C20 human microglial cell line was recently developed and our primary objective was to advance our knowledge of inflammatory signaling in these cells. Methods: Expression of the microglia specific marker transmembrane protein 119 (TMEM119) was assessed by western blot analysis. Lipopolysaccharide (LPS)-and interleukin-1β (IL-1β)-induced cytokine/chemokine expression was determined by ELISA. Phosphorylation of inhibitory kappa B alpha (IκBα), nuclear factor (NF)-κB p65, and p38 mitogen-activated protein kinase (p38 MAPK) was measured by western blot analysis. Results: TMEM119 was expressed in unstimulated C20 cells, and to a greater extent in IL-1β-stimulated cells. IL-1β significantly induced IL-6, monocyte chemoattractant protein-1/CCL2, and interferon-γ inducible protein 10/CXCL10 expression. LPS induced CCL2 expression, but not IL-6 or CXCL10 expression. IL-1β induced inflammatory signaling as indicated by increased phosphorylation of IκBα, NF-κB p65 and p38 MAPK. Conclusion: We provide the first evidence that C20 microglia express TMEM119. This is the initial report of IL-1βinduced activation of IκBα, NF-κB p65, and p38 MAPK and subsequent CXCL10, CCL2 and IL-6 secretion in C20 cells. These findings advance our understanding of inflammatory signaling in C20 cells and support the value of this cell line as a research tool.

show abstract

Section: Introductionmentioning

confidence: 99%

Interleukin-1β-induced inflammatory signaling in C20 human microglial cells

Davis¹,

Buck²,

McCracken³

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Under steady-state conditions, microglia are sessile cells but nevertheless show high motility of their processes to actively monitor their microenvironment in defined territories (Colonna & Butovsky, 2017;Shemer, Erny, Jung, & Prinz, 2015). Many of these functions depend on cell-cell communication via the CX3CL1/CX3CR1 chemokine signaling pathway (Cardona et al, 2006;Paolicelli et al, 2011;Werneburg, Feinberg, Johnson, & Schafer, 2017;Wolf, Yona, Kim, & Jung, 2013). They control neuronal survival, are involved in synaptic pruning, and constantly screen their environment for signs of damage or injury (Nayak, Roth, & McGavern, 2014;Parkhurst et al, 2013).…”

mentioning

confidence: 99%

“…They control neuronal survival, are involved in synaptic pruning, and constantly screen their environment for signs of damage or injury (Nayak, Roth, & McGavern, 2014;Parkhurst et al, 2013). Many of these functions depend on cell-cell communication via the CX3CL1/CX3CR1 chemokine signaling pathway (Cardona et al, 2006;Paolicelli et al, 2011;Werneburg, Feinberg, Johnson, & Schafer, 2017;Wolf, Yona, Kim, & Jung, 2013). Upon activation through danger-or microbeassociated molecular patterns and/or proinflammatory cytokines microglia retract their processes, round up, decrease their cell surface area, and increase their phagocytic capacity to remove dying cells or protein aggregates (Heneka et al, 2012;Nayak et al, 2014;Takahashi, Rochford, & Neumann, 2005).…”

mentioning

confidence: 99%

CCL17 exerts a neuroimmune modulatory function and is expressed in hippocampal neurons

Fülle

Offermann

Hansen

et al. 2018

Glia

View full text Add to dashboard Cite

Chemokines are important signaling molecules in the immune and nervous system. Using a fluorescence reporter mouse model, we demonstrate that the chemokine CCL17, a ligand of the chemokine receptor CCR4, is produced in the murine brain, particularly in a subset of hippocampal CA1 neurons. We found that basal expression of Ccl17 in hippocampal neurons was strongly enhanced by peripheral challenge with lipopolysaccharide (LPS). LPS‐mediated induction of Ccl17 in the hippocampus was dependent on local tumor necrosis factor (TNF) signaling, whereas upregulation of Ccl22 required granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). CCL17 deficiency resulted in a diminished microglia density under homeostatic and inflammatory conditions. Further, microglia from naïve Ccl17‐deficient mice possessed a reduced cellular volume and a more polarized process tree as assessed by computer‐assisted imaging analysis. Regarding the overall branching, cell surface area, and total tree length, the morphology of microglia from naïve Ccl17‐deficient mice resembled that of microglia from wild‐type mice after LPS stimulation. In line, electrophysiological recordings indicated that CCL17 downmodulates basal synaptic transmission at CA3–CA1 Schaffer collaterals in acute slices from naïve but not LPS‐treated animals. Taken together, our data identify CCL17 as a homeostatic and inducible neuromodulatory chemokine affecting the presence and morphology of microglia and synaptic transmission in the hippocampus.

show abstract

“…In contrast, only low expression levels of TNF-α and IL-6 were detected in the microglial cells 6 and 12 hours following infection with ZIKV ( Fig 2 ). Moreover, the expression of CX3CR1, an important regulator of microglia function at the neuronal synapse [ 31 ] was gradually upregulated in ZIKV-infected microglial cells 6, 12, 24 and 48 hpi, as compared to mock-infected cells ( Fig 2 ).…”

Section: Resultsmentioning

confidence: 99%

Zika virus infection modulates the metabolomic profile of microglial cells

et al. 2018

View full text Add to dashboard Cite

Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family. Although infection with ZIKV generally leads to mild disease, its recent emergence in the Americas has been associated with an increase in the development of the Guillain-Barré syndrome in adults, as well as with neurological complications, in particular congenital microcephaly, in new-borns. To date, little information is available on neuroinflammation induced by ZIKV, notably in microglial cells in the context of their metabolic activity, a series of chemical transformations that are essential for their growth, reproduction, structural maintenance and environmental responses. Therefore, in the present study we investigated the metabolomic profile of ZIKV-infected microglia. Microglial cells were exposed to ZIKV at different time points and were analyzed by a Liquid Chromatography-High Resolution mass spectrometry-based metabolomic approach. The results show that ZIKV infection in microglia leads to modulation of the expression of numerous metabolites, including lysophospholipids, particulary Lysophosphatidylcholine, and phospholipids such as Phosphatidylcholine, Phosphatidylserine, Ceramide and Sphingomyelin, and carboxylicic acids as Undecanedioic and Dodecanedioic acid. Some of these metabolites are involved in neuronal differentiation, regulation of apoptosis, virion architecture and viral replication. ZIKV infection was associated with concomitant secretion of inflammatory mediators linked with central nervous system inflammation such as IL-6, TNF-α, IL-1β, iNOS and NO. It also resulted in the upregulation of the expression of the gene encoding CX3CR1, a chemokine receptor known to regulate functional synapse plasticity and signaling between microglial cells. These findings highlight an important role for microglia and their metabolites in the process of neuroinflammation that occurs during ZIKV pathogenesis.

show abstract

A microglia-cytokine axis to modulate synaptic connectivity and function

Cited by 97 publications

References 65 publications

Interleukin-1β-induced inflammatory signaling in C20 human microglial cells

Interleukin-1β-induced inflammatory signaling in C20 human microglial cells

CCL17 exerts a neuroimmune modulatory function and is expressed in hippocampal neurons

Zika virus infection modulates the metabolomic profile of microglial cells

Contact Info

Product

Resources

About