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J Neuroinflammation. 2014 Nov 6;11:183. doi: 10.1186/s12974-014-0183-6.

Metabolic consequences of interleukin-6 challenge in developing neurons and astroglia.

Brown JA1,2, Sherrod SD3,4, Goodwin CR5,6, Brewer B7, Yang L8, Garbett KA9, Li D10,11, McLean JA12,13, Wikswo JP14,15,16,17, Mirnics K18,19,20,21.

Author information

1
Department of Psychiatry, 465 21st Avenue South, Vanderbilt University, Nashville, TN, 37232, USA. jacquelyn.a.brown@vanderbilt.edu.
2
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. jacquelyn.a.brown@vanderbilt.edu.
3
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. stacy.d.sherrod@vanderbilt.edu.
4
Department of Physics and Astronomy, 6301 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. stacy.d.sherrod@vanderbilt.edu.
5
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. cody.r.goodwin@vanderbilt.edu.
6
Department of Chemistry, 5421 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. cody.r.goodwin@vanderbilt.edu.
7
Department of Mechanical Engineering, 333 Olin Hall, Vanderbilt University, Nashville, TN, 37235, USA. bryson.brewer@vanderbilt.edu.
8
Department of Mechanical Engineering, 333 Olin Hall, Vanderbilt University, Nashville, TN, 37235, USA. lijie.yang@vanderbilt.edu.
9
Department of Psychiatry, 465 21st Avenue South, Vanderbilt University, Nashville, TN, 37232, USA. krassimira.garbett@vanderbilt.edu.
10
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. deyu.li@vanderbilt.edu.
11
Department of Mechanical Engineering, 333 Olin Hall, Vanderbilt University, Nashville, TN, 37235, USA. deyu.li@vanderbilt.edu.
12
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. john.a.mclean@vanderbilt.edu.
13
Department of Chemistry, 5421 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. john.a.mclean@vanderbilt.edu.
14
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. john.wikswo@vanderbilt.edu.
15
Department of Physics and Astronomy, 6301 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. john.wikswo@vanderbilt.edu.
16
Department of Biomedical Engineering, 5824 Stevenson Center, Vanderbilt University, Nashville, 37235, TN, USA. john.wikswo@vanderbilt.edu.
17
Department of Molecular Physiology and Biophysics, 702 Light Hall, Vanderbilt University, Nashville, TN, 37232, USA. john.wikswo@vanderbilt.edu.
18
Department of Psychiatry, 465 21st Avenue South, Vanderbilt University, Nashville, TN, 37232, USA. karoly.mirnics@vanderbilt.edu.
19
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. karoly.mirnics@vanderbilt.edu.
20
Vanderbilt Kennedy Center for Research on Human Development, 110 Magnolia Circle, Vanderbilt University, Nashville, TN, 37203, USA. karoly.mirnics@vanderbilt.edu.
21
Department of Psychiatry, University of Szeged, 6725, Szeged, Hungary. karoly.mirnics@vanderbilt.edu.

Abstract

BACKGROUND:

Maternal immune activation and subsequent interleukin-6 (IL-6) induction disrupt normal brain development and predispose the offspring to developing autism and schizophrenia. While several proteins have been identified as having some link to these developmental disorders, their prevalence is still small and their causative role, if any, is not well understood. However, understanding the metabolic consequences of environmental predisposing factors could shed light on disorders such as autism and schizophrenia.

METHODS:

To gain a better understanding of the metabolic consequences of IL-6 exposure on developing central nervous system (CNS) cells, we separately exposed developing neuron and astroglia cultures to IL-6 for 2 hours while collecting effluent from our gravity-fed microfluidic chambers. By coupling microfluidic technologies to ultra-performance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS), we were able to characterize the metabolic response of these CNS cells to a narrow window of IL-6 exposure.

RESULTS:

Our results revealed that 1) the use of this technology, due to its superb media volume:cell volume ratio, is ideally suited for analysis of cell-type-specific exometabolome signatures; 2) developing neurons have low secretory activity at baseline, while astroglia show strong metabolic activity; 3) both neurons and astroglia respond to IL-6 exposure in a cell type-specific fashion; 4) the astroglial response to IL-6 stimulation is predominantly characterized by increased levels of metabolites, while neurons mostly depress their metabolic activity; and 5) disturbances in glycerophospholipid metabolism and tryptophan/kynurenine metabolite secretion are two putative mechanisms by which IL-6 affects the developing nervous system.

CONCLUSIONS:

Our findings are potentially critical for understanding the mechanism by which IL-6 disrupts brain function, and they provide information about the molecular cascade that links maternal immune activation to developmental brain disorders.

PMID:
25374324
PMCID:
PMC4233071
DOI:
10.1186/s12974-014-0183-6
[Indexed for MEDLINE]
Free PMC Article

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