Metabolic consequences of interleukin-6 challenge in developing neurons and astroglia.
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.
Department of Psychiatry, 465 21st Avenue South, Vanderbilt University, Nashville, TN, 37232, USA. jacquelyn.a.brown@vanderbilt.edu.|Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. jacquelyn.a.brown@vanderbilt.edu.
Jacquelyn A
JA
Brown
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. stacy.d.sherrod@vanderbilt.edu.|Department of Physics and Astronomy, 6301 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. stacy.d.sherrod@vanderbilt.edu.
Stacy D
SD
Sherrod
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. cody.r.goodwin@vanderbilt.edu.|Department of Chemistry, 5421 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. cody.r.goodwin@vanderbilt.edu.
Cody R
CR
Goodwin
Department of Mechanical Engineering, 333 Olin Hall, Vanderbilt University, Nashville, TN, 37235, USA. bryson.brewer@vanderbilt.edu.
Bryson
B
Brewer
Department of Mechanical Engineering, 333 Olin Hall, Vanderbilt University, Nashville, TN, 37235, USA. lijie.yang@vanderbilt.edu.
Lijie
L
Yang
Department of Psychiatry, 465 21st Avenue South, Vanderbilt University, Nashville, TN, 37232, USA. krassimira.garbett@vanderbilt.edu.
Krassimira A
KA
Garbett
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. deyu.li@vanderbilt.edu.|Department of Mechanical Engineering, 333 Olin Hall, Vanderbilt University, Nashville, TN, 37235, USA. deyu.li@vanderbilt.edu.
Deyu
D
Li
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. john.a.mclean@vanderbilt.edu.|Department of Chemistry, 5421 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. john.a.mclean@vanderbilt.edu.
John A
JA
McLean
Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. john.wikswo@vanderbilt.edu.|Department of Physics and Astronomy, 6301 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. john.wikswo@vanderbilt.edu.|Department of Biomedical Engineering, 5824 Stevenson Center, Vanderbilt University, Nashville, 37235, TN, USA. john.wikswo@vanderbilt.edu.|Department of Molecular Physiology and Biophysics, 702 Light Hall, Vanderbilt University, Nashville, TN, 37232, USA. john.wikswo@vanderbilt.edu.
John P
JP
Wikswo
Department of Psychiatry, 465 21st Avenue South, Vanderbilt University, Nashville, TN, 37232, USA. karoly.mirnics@vanderbilt.edu.|Vanderbilt Institute for Integrative Biosystems Research and Education, 6809 Stevenson Center, Vanderbilt University, Nashville, TN, 37235, USA. karoly.mirnics@vanderbilt.edu.|Vanderbilt Kennedy Center for Research on Human Development, 110 Magnolia Circle, Vanderbilt University, Nashville, TN, 37203, USA. karoly.mirnics@vanderbilt.edu.|Department of Psychiatry, University of Szeged, 6725, Szeged, Hungary. karoly.mirnics@vanderbilt.edu.
Károly
K
Mirnics
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D015850:Interleukin-6 / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046210:Microfluidic Analytical Techniques; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*
D015850:Interleukin-6