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

Mult Scler. 2021 Oct;27(12):1948-1959. doi: 10.1177/1352458521989090. Epub 2021 Feb 1.

Authors

Mukanthu H Nyirenda¹, Giulia Fadda², Luke M Healy³, Ina Mexhitaj², Laurence Poliquin-Lasnier⁴, Heather Hanwell⁵, Alexander W Saveriano³, Ayal Rozenberg⁶, Rui Li², Craig S Moore⁷, Chahrazed Belabani⁸, Trina Johnson⁸, Julia O'Mahony⁹, Douglas L Arnold³, E Ann Yeh¹⁰, Ruth Ann Marrie¹¹, Shannon Dunn¹², Brenda Banwell¹³, Amit Bar-Or¹⁴

Affiliations

¹ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada/Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
² Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada/Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁴ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada/Department of Neurology, Hull Hospital, Gatineau, QC, Canada.
⁵ Neurosciences and Mental Health, Hospital for Sick Children Research Institute, Toronto, ON, Canada/ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁶ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada/Neuroimmunology Unit, Rambam Health Care Campus, Haifa, Israel.
⁷ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada/Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
⁸ Experimental Therapeutics Program, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
⁹ Neurosciences and Mental Health, Hospital for Sick Children Research Institute, Toronto, ON, Canada.
¹⁰ Division of Neurology, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Departments of Internal Medicine and Community Health Sciences, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MN, Canada.
¹² Keenan Research Centre for Biomedical Science, Toronto, ON, Canada/Department of Immunology, University of Toronto, Toronto, ON, Canada.
¹³ Neurosciences and Mental Health, Hospital for Sick Children Research Institute, Toronto, ON, Canada/Division of Neurology, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada/Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada/Experimental Therapeutics Program, Montreal Neurological Institute, McGill University, Montreal, QC, Canada/Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

PMID: 33522403
DOI: 10.1177/1352458521989090

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: Multiple sclerosis; adipokines; adiponectin; immune responses; myelin oligodendrocyte glycoprotein; pediatric multiple sclerosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipokines
Adiponectin*
CD8-Positive T-Lymphocytes
Child
Humans
Microglia
Multiple Sclerosis*

Substances

Adipokines
Adiponectin

Grants and funding

CIHR/Canada