Neurotrophin-3 attenuates human peripheral blood T cell and monocyte activation status and cytokine production post stroke

Mark Lukas Müller; Lars Peglau; Lawrence D.F. Moon; Stefan Groß; Juliane Schulze; Johanna Ruhnau; Antje Vogelgesang

doi:10.1016/j.expneurol.2021.113901

Neurotrophin-3 attenuates human peripheral blood T cell and monocyte activation status and cytokine production post stroke

Mark Lukas Müller, Lars Peglau, Lawrence D.F. Moon, Stefan Groß, Juliane Schulze, Johanna Ruhnau, Antje Vogelgesang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE: Stroke therapy still lacks successful measures to improve post stroke recovery. Neurotrophin-3 (NT-3) is one promising candidate which has proven therapeutic benefit in motor recovery in acute experimental stroke. Post stroke, the immune system has opposing pathophysiological roles: pro-inflammatory cascades and immune cell infiltration into the brain exacerbate cell death while the peripheral immune response has only limited capabilities to fight infections during the acute and subacute phase. With time, anti-inflammatory mechanisms are supposed to support recovery of the ischemic damage within the brain parenchyma. However, interestingly, NT-3 can improve recovery in chronic neurological injury when combined with the pro-inflammatory stimulus lipopolysaccharide (LPS).

AIM: We elucidated the impact of NT-3 on human monocyte and T cell activation as well as cytokine production ex vivo after stroke. In addition, we investigated the age-dependent availability of the high affinity NT-3 receptor TrkC upon LPS stimulation.

METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from acute stroke patients and controls and incubated with different dosages of NT-3 (10 and 100 ng/mL) and with or without LPS or anti-CD3/CD28 for 48 h. Total TrkC expression and cell activation (CD25, CD69 and HLA-DR) were assessed by FACS staining. IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21 and IL-22 were quantified by cytometric bead array.

RESULTS: Most monocytes and only a small proportion of T cells expressed TrkC in blood from humans without stroke. Activation of cells from young humans (without strokes) using anti-CD3/CD28 or LPS partially reduced the proportion of monocytes expressing TrkC whilst they increased the proportion of T cells expressing TrkC. In contrast, activation of cells from elderly humans (without strokes) did not affect the proportion of monocytes expressing TrkC and only anti-CD3/CD28 led to an increase in the proportion of CD4+ T cells expressing TrkC. In blood from stroke patients or controls, NT-3 treatment reduced the percentage of monocytes and CD4+ and CD8+ T cells that were activated and reduced all cytokines investigated besides IL-21.

CONCLUSIONS: NT-3 attenuated immune responses in cells from stroke patients and controls. The mechanism whereby human immune cells respond to NT-3 may be via TrkC receptors whose levels are regulated by stimulation. Further work is required to determine whether the induction of sensorimotor recovery in rodents by NT-3 after CNS injury is caused by this attenuation of the immune response.

Original language	English
Article number	113901
Journal	Experimental Neurology
Volume	347
Early online date	22 Oct 2021
DOIs	https://doi.org/10.1016/j.expneurol.2021.113901
Publication status	Published - Jan 2022

Keywords

Cytokine
NT-3
Stroke
T cell
TrkC

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10.1016/j.expneurol.2021.113901

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@article{9590537c951d4267b49bae69e874e4a1,

title = "Neurotrophin-3 attenuates human peripheral blood T cell and monocyte activation status and cytokine production post stroke",

abstract = "BACKGROUND AND PURPOSE: Stroke therapy still lacks successful measures to improve post stroke recovery. Neurotrophin-3 (NT-3) is one promising candidate which has proven therapeutic benefit in motor recovery in acute experimental stroke. Post stroke, the immune system has opposing pathophysiological roles: pro-inflammatory cascades and immune cell infiltration into the brain exacerbate cell death while the peripheral immune response has only limited capabilities to fight infections during the acute and subacute phase. With time, anti-inflammatory mechanisms are supposed to support recovery of the ischemic damage within the brain parenchyma. However, interestingly, NT-3 can improve recovery in chronic neurological injury when combined with the pro-inflammatory stimulus lipopolysaccharide (LPS).AIM: We elucidated the impact of NT-3 on human monocyte and T cell activation as well as cytokine production ex vivo after stroke. In addition, we investigated the age-dependent availability of the high affinity NT-3 receptor TrkC upon LPS stimulation.METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from acute stroke patients and controls and incubated with different dosages of NT-3 (10 and 100 ng/mL) and with or without LPS or anti-CD3/CD28 for 48 h. Total TrkC expression and cell activation (CD25, CD69 and HLA-DR) were assessed by FACS staining. IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21 and IL-22 were quantified by cytometric bead array.RESULTS: Most monocytes and only a small proportion of T cells expressed TrkC in blood from humans without stroke. Activation of cells from young humans (without strokes) using anti-CD3/CD28 or LPS partially reduced the proportion of monocytes expressing TrkC whilst they increased the proportion of T cells expressing TrkC. In contrast, activation of cells from elderly humans (without strokes) did not affect the proportion of monocytes expressing TrkC and only anti-CD3/CD28 led to an increase in the proportion of CD4+ T cells expressing TrkC. In blood from stroke patients or controls, NT-3 treatment reduced the percentage of monocytes and CD4+ and CD8+ T cells that were activated and reduced all cytokines investigated besides IL-21.CONCLUSIONS: NT-3 attenuated immune responses in cells from stroke patients and controls. The mechanism whereby human immune cells respond to NT-3 may be via TrkC receptors whose levels are regulated by stimulation. Further work is required to determine whether the induction of sensorimotor recovery in rodents by NT-3 after CNS injury is caused by this attenuation of the immune response.",

keywords = "Cytokine, NT-3, Stroke, T cell, TrkC",

author = "M{\"u}ller, {Mark Lukas} and Lars Peglau and Moon, {Lawrence D.F.} and Stefan Gro{\ss} and Juliane Schulze and Johanna Ruhnau and Antje Vogelgesang",

note = "Funding Information: The experiments were funded by a grant to LM and AV from Brain Research UK (201617–04). AV received funding from the University of Greifswald – K{\"a}the-Kluth-Research-Group. JR was funded by the Gerhard-Domagk-Program of the University Medicine Greifswald . LM received funding from the Medical Research Council ( MR/S026053/1 ). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the article. Funding Information: The experiments were funded by a grant to LM and AV from Brain Research UK (201617?04). AV received funding from the University of Greifswald ? K?the-Kluth-Research-Group. JR was funded by the Gerhard-Domagk-Program of the University Medicine Greifswald. LM received funding from the Medical Research Council (MR/S026053/1). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the article. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = jan,

doi = "10.1016/j.expneurol.2021.113901",

language = "English",

volume = "347",

journal = "Experimental Neurology",

issn = "0014-4886",

publisher = "ACADEMIC PRESS INC",

}

TY - JOUR

T1 - Neurotrophin-3 attenuates human peripheral blood T cell and monocyte activation status and cytokine production post stroke

AU - Müller, Mark Lukas

AU - Peglau, Lars

AU - Moon, Lawrence D.F.

AU - Groß, Stefan

AU - Schulze, Juliane

AU - Ruhnau, Johanna

AU - Vogelgesang, Antje

N1 - Funding Information: The experiments were funded by a grant to LM and AV from Brain Research UK (201617–04). AV received funding from the University of Greifswald – Käthe-Kluth-Research-Group. JR was funded by the Gerhard-Domagk-Program of the University Medicine Greifswald . LM received funding from the Medical Research Council ( MR/S026053/1 ). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the article. Funding Information: The experiments were funded by a grant to LM and AV from Brain Research UK (201617?04). AV received funding from the University of Greifswald ? K?the-Kluth-Research-Group. JR was funded by the Gerhard-Domagk-Program of the University Medicine Greifswald. LM received funding from the Medical Research Council (MR/S026053/1). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the article. Publisher Copyright: © 2021 The Authors

PY - 2022/1

Y1 - 2022/1

N2 - BACKGROUND AND PURPOSE: Stroke therapy still lacks successful measures to improve post stroke recovery. Neurotrophin-3 (NT-3) is one promising candidate which has proven therapeutic benefit in motor recovery in acute experimental stroke. Post stroke, the immune system has opposing pathophysiological roles: pro-inflammatory cascades and immune cell infiltration into the brain exacerbate cell death while the peripheral immune response has only limited capabilities to fight infections during the acute and subacute phase. With time, anti-inflammatory mechanisms are supposed to support recovery of the ischemic damage within the brain parenchyma. However, interestingly, NT-3 can improve recovery in chronic neurological injury when combined with the pro-inflammatory stimulus lipopolysaccharide (LPS).AIM: We elucidated the impact of NT-3 on human monocyte and T cell activation as well as cytokine production ex vivo after stroke. In addition, we investigated the age-dependent availability of the high affinity NT-3 receptor TrkC upon LPS stimulation.METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from acute stroke patients and controls and incubated with different dosages of NT-3 (10 and 100 ng/mL) and with or without LPS or anti-CD3/CD28 for 48 h. Total TrkC expression and cell activation (CD25, CD69 and HLA-DR) were assessed by FACS staining. IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21 and IL-22 were quantified by cytometric bead array.RESULTS: Most monocytes and only a small proportion of T cells expressed TrkC in blood from humans without stroke. Activation of cells from young humans (without strokes) using anti-CD3/CD28 or LPS partially reduced the proportion of monocytes expressing TrkC whilst they increased the proportion of T cells expressing TrkC. In contrast, activation of cells from elderly humans (without strokes) did not affect the proportion of monocytes expressing TrkC and only anti-CD3/CD28 led to an increase in the proportion of CD4+ T cells expressing TrkC. In blood from stroke patients or controls, NT-3 treatment reduced the percentage of monocytes and CD4+ and CD8+ T cells that were activated and reduced all cytokines investigated besides IL-21.CONCLUSIONS: NT-3 attenuated immune responses in cells from stroke patients and controls. The mechanism whereby human immune cells respond to NT-3 may be via TrkC receptors whose levels are regulated by stimulation. Further work is required to determine whether the induction of sensorimotor recovery in rodents by NT-3 after CNS injury is caused by this attenuation of the immune response.

AB - BACKGROUND AND PURPOSE: Stroke therapy still lacks successful measures to improve post stroke recovery. Neurotrophin-3 (NT-3) is one promising candidate which has proven therapeutic benefit in motor recovery in acute experimental stroke. Post stroke, the immune system has opposing pathophysiological roles: pro-inflammatory cascades and immune cell infiltration into the brain exacerbate cell death while the peripheral immune response has only limited capabilities to fight infections during the acute and subacute phase. With time, anti-inflammatory mechanisms are supposed to support recovery of the ischemic damage within the brain parenchyma. However, interestingly, NT-3 can improve recovery in chronic neurological injury when combined with the pro-inflammatory stimulus lipopolysaccharide (LPS).AIM: We elucidated the impact of NT-3 on human monocyte and T cell activation as well as cytokine production ex vivo after stroke. In addition, we investigated the age-dependent availability of the high affinity NT-3 receptor TrkC upon LPS stimulation.METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from acute stroke patients and controls and incubated with different dosages of NT-3 (10 and 100 ng/mL) and with or without LPS or anti-CD3/CD28 for 48 h. Total TrkC expression and cell activation (CD25, CD69 and HLA-DR) were assessed by FACS staining. IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21 and IL-22 were quantified by cytometric bead array.RESULTS: Most monocytes and only a small proportion of T cells expressed TrkC in blood from humans without stroke. Activation of cells from young humans (without strokes) using anti-CD3/CD28 or LPS partially reduced the proportion of monocytes expressing TrkC whilst they increased the proportion of T cells expressing TrkC. In contrast, activation of cells from elderly humans (without strokes) did not affect the proportion of monocytes expressing TrkC and only anti-CD3/CD28 led to an increase in the proportion of CD4+ T cells expressing TrkC. In blood from stroke patients or controls, NT-3 treatment reduced the percentage of monocytes and CD4+ and CD8+ T cells that were activated and reduced all cytokines investigated besides IL-21.CONCLUSIONS: NT-3 attenuated immune responses in cells from stroke patients and controls. The mechanism whereby human immune cells respond to NT-3 may be via TrkC receptors whose levels are regulated by stimulation. Further work is required to determine whether the induction of sensorimotor recovery in rodents by NT-3 after CNS injury is caused by this attenuation of the immune response.

KW - Cytokine

KW - NT-3

KW - Stroke

KW - T cell

KW - TrkC

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U2 - 10.1016/j.expneurol.2021.113901

DO - 10.1016/j.expneurol.2021.113901

M3 - Article

C2 - 34688600

AN - SCOPUS:85117924322

SN - 0014-4886

VL - 347

JO - Experimental Neurology

JF - Experimental Neurology

M1 - 113901

ER -

Neurotrophin-3 attenuates human peripheral blood T cell and monocyte activation status and cytokine production post stroke

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Keywords

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