Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis

Mukanthu H. Nyirenda; Giulia Fadda; Luke M. Healy; Ina Mexhitaj; Laurence Poliquin-Lasnier; Heather Hanwell; Alexander W. Saveriano; Ayal Rozenberg; Rui Li; Craig S. Moore; Chahrazed Belabani; Trina Johnson; Julia O’Mahony; Douglas L. Arnold; E. Ann Yeh; Ruth Ann Marrie; Shannon Dunn; Brenda Banwell; Amit Bar-Or;

doi:10.1177/1352458521989090

Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis

Mukanthu H. Nyirenda, Giulia Fadda, Luke M. Healy, Ina Mexhitaj, Laurence Poliquin-Lasnier, Heather Hanwell, Alexander W. Saveriano, Ayal Rozenberg, Rui Li, Craig S. Moore, Chahrazed Belabani, Trina Johnson, Julia O’Mahony, Douglas L. Arnold, E. Ann Yeh, Ruth Ann Marrie, Shannon Dunn, Brenda Banwell, Amit Bar-Or;

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

Abstract

Background: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. Objectives: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. Methods: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. Results: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14⁺ monocytes and of activated CD4⁺ and CD8⁺ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. Conclusions: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.

Original language	English
Pages (from-to)	1948-1959
Number of pages	12
Journal	Multiple Sclerosis Journal
Volume	27
Issue number	12
DOIs	https://doi.org/10.1177/1352458521989090
Publication status	Published - Oct 2021
Externally published	Yes

Keywords

adipokines
adiponectin
immune responses
Multiple sclerosis
myelin oligodendrocyte glycoprotein
pediatric multiple sclerosis

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1177/1352458521989090

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Nyirenda, M. H., Fadda, G., Healy, L. M., Mexhitaj, I., Poliquin-Lasnier, L., Hanwell, H., Saveriano, A. W., Rozenberg, A., Li, R., Moore, C. S., Belabani, C., Johnson, T., O’Mahony, J., Arnold, D. L., Yeh, E. A., Marrie, R. A., Dunn, S., Banwell, B., & Bar-Or;, A. (2021). Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis. Multiple Sclerosis Journal, 27(12), 1948-1959. https://doi.org/10.1177/1352458521989090

Nyirenda, MH, Fadda, G, Healy, LM, Mexhitaj, I, Poliquin-Lasnier, L, Hanwell, H, Saveriano, AW, Rozenberg, A, Li, R, Moore, CS, Belabani, C, Johnson, T, O’Mahony, J, Arnold, DL, Yeh, EA, Marrie, RA, Dunn, S, Banwell, B & Bar-Or;, A 2021, 'Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis', Multiple Sclerosis Journal, vol. 27, no. 12, pp. 1948-1959. https://doi.org/10.1177/1352458521989090

@article{d19bde9ca2794b1b980a036cab4774ac,

title = "Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis",

abstract = "Background: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. Objectives: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. Methods: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. Results: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. Conclusions: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.",

keywords = "adipokines, adiponectin, immune responses, Multiple sclerosis, myelin oligodendrocyte glycoprotein, pediatric multiple sclerosis",

author = "Nyirenda, {Mukanthu H.} and Giulia Fadda and Healy, {Luke M.} and Ina Mexhitaj and Laurence Poliquin-Lasnier and Heather Hanwell and Saveriano, {Alexander W.} and Ayal Rozenberg and Rui Li and Moore, {Craig S.} and Chahrazed Belabani and Trina Johnson and Julia O{\textquoteright}Mahony and Arnold, {Douglas L.} and Yeh, {E. Ann} and Marrie, {Ruth Ann} and Shannon Dunn and Brenda Banwell and Amit Bar-Or;",

note = "Funding Information: The authors acknowledge the site investigators: Drs Katherine Wambera, Mary B Connolly, Jerome Yager, Jean K Mah, Fran Booth, Guillaume Sebire, David Callen, Brandon Meaney, Marie-Emmanuelle Dilenge, Anne Lortie, Daniela Pohl, Asif Doja, Sunita Venkateswaran, Simon Levin, E Athen MacDonald, David Meek, Ellen Wood, Noel Lowry, David Buckley, Conrad Yim, Mark Awuku, Pamela Cooper, Francois Grand?Maison, J Burke Baird, and Virender Bhan. The authors also wish to acknowledge the invaluable assistance of the coordinator(s) at each site, as well as Ms Rozie Arnaoutelis and Ms Danusha Nandamalvan, and the important contribution of the Experimental Therapeutics Program team members at the Montreal Neurological Institute for judicious handling of patient and control samples. They also thank the participating children and their families. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded in part by the Multiple Sclerosis Scientific Research Foundation (E.A.Y., R.A.M., D.L.A., B.B., and A.B.O.) and the University of Pennsylvania Center for Neuroinflammation and Neurotherapeutics (A.B.O.). M.N. was supported by an MSSOC Research Fellowship. G.F. was funded by the Clinical Research Training Scholarship in Multiple Sclerosis from the American Academy of Neurology. I.M. was supported by the Canadian Institutes of Health Research (CIHR) Vanier Graduate Scholarship, the CIHR Training Grant in Neuroinflammation, and the Neuroscience Graduate Group, University of Pennsylvania. R.L. was supported by the Banque Nationale Fellowship; J.O.M. was supported by the Waugh Family Multiple Sclerosis Society of Canada Doctoral Studentship award. B.B. was funded by the National MS Society, NIH, and the Multiple Sclerosis Society of Canada. A.B.O. was funded by the NIH, Immune Tolerance Network (ITN), National MS Society, and the Multiple Sclerosis Society of Canada. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded in part by the Multiple Sclerosis Scientific Research Foundation (E.A.Y., R.A.M., D.L.A., B.B., and A.B.O.) and the University of Pennsylvania Center for Neuroinflammation and Neurotherapeutics (A.B.O.). M.N. was supported by an MSSOC Research Fellowship. G.F. was funded by the Clinical Research Training Scholarship in Multiple Sclerosis from the American Academy of Neurology. I.M. was supported by the Canadian Institutes of Health Research (CIHR) Vanier Graduate Scholarship, the CIHR Training Grant in Neuroinflammation, and the Neuroscience Graduate Group, University of Pennsylvania. R.L. was supported by the Banque Nationale Fellowship; J.O.M. was supported by the Waugh Family Multiple Sclerosis Society of Canada Doctoral Studentship award. B.B. was funded by the National MS Society, NIH, and the Multiple Sclerosis Society of Canada. A.B.O. was funded by the NIH, Immune Tolerance Network (ITN), National MS Society, and the Multiple Sclerosis Society of Canada. Publisher Copyright: {\textcopyright} The Author(s), 2021.",

year = "2021",

month = oct,

doi = "10.1177/1352458521989090",

language = "English",

volume = "27",

pages = "1948--1959",

journal = "Multiple Sclerosis",

issn = "1352-4585",

publisher = "SAGE Publications Ltd",

number = "12",

}

TY - JOUR

T1 - Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis

AU - Nyirenda, Mukanthu H.

AU - Fadda, Giulia

AU - Healy, Luke M.

AU - Mexhitaj, Ina

AU - Poliquin-Lasnier, Laurence

AU - Hanwell, Heather

AU - Saveriano, Alexander W.

AU - Rozenberg, Ayal

AU - Li, Rui

AU - Moore, Craig S.

AU - Belabani, Chahrazed

AU - Johnson, Trina

AU - O’Mahony, Julia

AU - Arnold, Douglas L.

AU - Yeh, E. Ann

AU - Marrie, Ruth Ann

AU - Dunn, Shannon

AU - Banwell, Brenda

AU - Bar-Or;, Amit

N1 - Funding Information: The authors acknowledge the site investigators: Drs Katherine Wambera, Mary B Connolly, Jerome Yager, Jean K Mah, Fran Booth, Guillaume Sebire, David Callen, Brandon Meaney, Marie-Emmanuelle Dilenge, Anne Lortie, Daniela Pohl, Asif Doja, Sunita Venkateswaran, Simon Levin, E Athen MacDonald, David Meek, Ellen Wood, Noel Lowry, David Buckley, Conrad Yim, Mark Awuku, Pamela Cooper, Francois Grand?Maison, J Burke Baird, and Virender Bhan. The authors also wish to acknowledge the invaluable assistance of the coordinator(s) at each site, as well as Ms Rozie Arnaoutelis and Ms Danusha Nandamalvan, and the important contribution of the Experimental Therapeutics Program team members at the Montreal Neurological Institute for judicious handling of patient and control samples. They also thank the participating children and their families. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded in part by the Multiple Sclerosis Scientific Research Foundation (E.A.Y., R.A.M., D.L.A., B.B., and A.B.O.) and the University of Pennsylvania Center for Neuroinflammation and Neurotherapeutics (A.B.O.). M.N. was supported by an MSSOC Research Fellowship. G.F. was funded by the Clinical Research Training Scholarship in Multiple Sclerosis from the American Academy of Neurology. I.M. was supported by the Canadian Institutes of Health Research (CIHR) Vanier Graduate Scholarship, the CIHR Training Grant in Neuroinflammation, and the Neuroscience Graduate Group, University of Pennsylvania. R.L. was supported by the Banque Nationale Fellowship; J.O.M. was supported by the Waugh Family Multiple Sclerosis Society of Canada Doctoral Studentship award. B.B. was funded by the National MS Society, NIH, and the Multiple Sclerosis Society of Canada. A.B.O. was funded by the NIH, Immune Tolerance Network (ITN), National MS Society, and the Multiple Sclerosis Society of Canada. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded in part by the Multiple Sclerosis Scientific Research Foundation (E.A.Y., R.A.M., D.L.A., B.B., and A.B.O.) and the University of Pennsylvania Center for Neuroinflammation and Neurotherapeutics (A.B.O.). M.N. was supported by an MSSOC Research Fellowship. G.F. was funded by the Clinical Research Training Scholarship in Multiple Sclerosis from the American Academy of Neurology. I.M. was supported by the Canadian Institutes of Health Research (CIHR) Vanier Graduate Scholarship, the CIHR Training Grant in Neuroinflammation, and the Neuroscience Graduate Group, University of Pennsylvania. R.L. was supported by the Banque Nationale Fellowship; J.O.M. was supported by the Waugh Family Multiple Sclerosis Society of Canada Doctoral Studentship award. B.B. was funded by the National MS Society, NIH, and the Multiple Sclerosis Society of Canada. A.B.O. was funded by the NIH, Immune Tolerance Network (ITN), National MS Society, and the Multiple Sclerosis Society of Canada. Publisher Copyright: © The Author(s), 2021.

PY - 2021/10

Y1 - 2021/10

N2 - Background: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. Objectives: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. Methods: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. Results: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. Conclusions: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.

AB - Background: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. Objectives: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. Methods: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. Results: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. Conclusions: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.

KW - adipokines

KW - adiponectin

KW - immune responses

KW - Multiple sclerosis

KW - myelin oligodendrocyte glycoprotein

KW - pediatric multiple sclerosis

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UR - http://www.scopus.com/inward/citedby.url?scp=85100516217&partnerID=8YFLogxK

U2 - 10.1177/1352458521989090

DO - 10.1177/1352458521989090

M3 - Article

C2 - 33522403

AN - SCOPUS:85100516217

SN - 1352-4585

VL - 27

SP - 1948

EP - 1959

JO - Multiple Sclerosis

JF - Multiple Sclerosis

IS - 12

ER -

Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis

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Keywords

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