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

Brown JA, Sherrod SD, Goodwin CR, Brewer B, Yang L, Garbett KA, Li D, McLean JA, Wikswo JP, Mirnics K - J Neuroinflammation (2014)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, 465 21st Avenue South, Vanderbilt University, Nashville, TN, 37232, USA. jacquelyn.a.brown@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.

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Related in: MedlinePlus

Alterations to the kynurenine pathway after IL-6 treatment. High energy (fragmentation) mass spectra for (A)m/z 209.10 (kynurenine) and (B)m/z 166.05 (formylanthranilate). Spectra were mobility separated to isolate only product ions for 209 and 166, respectively. (A) In astrocyte cultures, we observed a decrease in normalized ion signal after IL-6 treatment, ALR = −0.86, P <0.00001, for kynurenine (m/z 209.10). (B) In contrast, we observed an increase in ion signal for formylanthranilate (m/z 166.05), also a component of the kynurenine pathway, when neuronal cultures were treated with IL-6, ALR = 2.47, P <0.001. Taken together, these data show that IL-6 exposure alters both neurons and astrocytes but does so in an opposite manner.
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Fig5: Alterations to the kynurenine pathway after IL-6 treatment. High energy (fragmentation) mass spectra for (A)m/z 209.10 (kynurenine) and (B)m/z 166.05 (formylanthranilate). Spectra were mobility separated to isolate only product ions for 209 and 166, respectively. (A) In astrocyte cultures, we observed a decrease in normalized ion signal after IL-6 treatment, ALR = −0.86, P <0.00001, for kynurenine (m/z 209.10). (B) In contrast, we observed an increase in ion signal for formylanthranilate (m/z 166.05), also a component of the kynurenine pathway, when neuronal cultures were treated with IL-6, ALR = 2.47, P <0.001. Taken together, these data show that IL-6 exposure alters both neurons and astrocytes but does so in an opposite manner.

Mentions: In addition, in both neuronal and astroglial cultures we observed IL-6-induced exometabolome changes in the tryptophan-kynurenine pathway, a pathway strongly modulated by IL-6 activity in the brain. Kynurenine (m/z = 209.10, RT = 78 s) was observed to decrease in astroglial cultures in response to IL-6 exposure (Figure 5A, ALR = −0.86, P <0.00001), whereas formylanthranilate (m/z = 166.07, RT =70 s) was observed to increase in neuronal cultures in response to IL-6 exposure (Figure 5B, ALR = 2.47, P <0.001). Formylanthranilate is a downstream metabolite in the kynurenine pathway that yields neuroactive intermediates and has implications in the modulation of neurotransmitter systems [43]. Importantly, both formylanthranilate and kynurenine are part of the tryptophan-kynurenine metabolic pathway, and disturbances of this pathway are considered common mediators of genetic and environmental effects in major depressive disorder [44] and appear to contribute to schizophrenia pathophysiology [41,45]. Taken together, these data suggest that glycerophospholipid metabolism and tryptophan-kynurenine metabolite secretions are important (and potentially related) metabolic pathways by which IL-6 inflammation affects the developing nervous system and predisposes it to developing a brain disease.Figure 5


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

Brown JA, Sherrod SD, Goodwin CR, Brewer B, Yang L, Garbett KA, Li D, McLean JA, Wikswo JP, Mirnics K - J Neuroinflammation (2014)

Alterations to the kynurenine pathway after IL-6 treatment. High energy (fragmentation) mass spectra for (A)m/z 209.10 (kynurenine) and (B)m/z 166.05 (formylanthranilate). Spectra were mobility separated to isolate only product ions for 209 and 166, respectively. (A) In astrocyte cultures, we observed a decrease in normalized ion signal after IL-6 treatment, ALR = −0.86, P <0.00001, for kynurenine (m/z 209.10). (B) In contrast, we observed an increase in ion signal for formylanthranilate (m/z 166.05), also a component of the kynurenine pathway, when neuronal cultures were treated with IL-6, ALR = 2.47, P <0.001. Taken together, these data show that IL-6 exposure alters both neurons and astrocytes but does so in an opposite manner.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4233071&req=5

Fig5: Alterations to the kynurenine pathway after IL-6 treatment. High energy (fragmentation) mass spectra for (A)m/z 209.10 (kynurenine) and (B)m/z 166.05 (formylanthranilate). Spectra were mobility separated to isolate only product ions for 209 and 166, respectively. (A) In astrocyte cultures, we observed a decrease in normalized ion signal after IL-6 treatment, ALR = −0.86, P <0.00001, for kynurenine (m/z 209.10). (B) In contrast, we observed an increase in ion signal for formylanthranilate (m/z 166.05), also a component of the kynurenine pathway, when neuronal cultures were treated with IL-6, ALR = 2.47, P <0.001. Taken together, these data show that IL-6 exposure alters both neurons and astrocytes but does so in an opposite manner.
Mentions: In addition, in both neuronal and astroglial cultures we observed IL-6-induced exometabolome changes in the tryptophan-kynurenine pathway, a pathway strongly modulated by IL-6 activity in the brain. Kynurenine (m/z = 209.10, RT = 78 s) was observed to decrease in astroglial cultures in response to IL-6 exposure (Figure 5A, ALR = −0.86, P <0.00001), whereas formylanthranilate (m/z = 166.07, RT =70 s) was observed to increase in neuronal cultures in response to IL-6 exposure (Figure 5B, ALR = 2.47, P <0.001). Formylanthranilate is a downstream metabolite in the kynurenine pathway that yields neuroactive intermediates and has implications in the modulation of neurotransmitter systems [43]. Importantly, both formylanthranilate and kynurenine are part of the tryptophan-kynurenine metabolic pathway, and disturbances of this pathway are considered common mediators of genetic and environmental effects in major depressive disorder [44] and appear to contribute to schizophrenia pathophysiology [41,45]. Taken together, these data suggest that glycerophospholipid metabolism and tryptophan-kynurenine metabolite secretions are important (and potentially related) metabolic pathways by which IL-6 inflammation affects the developing nervous system and predisposes it to developing a brain disease.Figure 5

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, 465 21st Avenue South, Vanderbilt University, Nashville, TN, 37232, USA. jacquelyn.a.brown@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.

Show MeSH
Related in: MedlinePlus