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.

Differential impact of environmental factors on systemic and localized autoimmunity

“…( 91 ). The adiponectin hormone secreted by adipose tissue was found to be significantly abundant within the serum of children with MS (n=43, p<0.005) and appears to induce pro-inflammatory states of CD14 + monocytes through increased expression of CD80, CD86, TNF-α and IL-6, as well as the adaptive immune cells IFN-γ producing CD4 + and CD8 + T cells directly or via myeloid cells, and altering the quiescence profile of human microglia ( 92 ). Furthermore, adiponectin levels in the CSF and serum of MS patients appear to correlate with MS disease severity and progression and are higher compared to controls ( 93 – 96 ).…”

Preventing Multiple Sclerosis: The Pediatric Perspective

“…A recent study comparing 33 children with MS to 54 children with MOGAD, and 29 healthy controls, observed significantly higher levels of adiponectin in the serum of MS patients compared to both the MOGAD and healthy control patients (p = 0.02) (59). This study also investigated the functional consequence of elevated adiponectin on immune cells and discovered that adiponectin from the serum of pediatric MS patients led to pro-inflammatory responses in CD14+ monocytes, T-cell activation, upregulation of CNS microglia proinflammatory markers, and downregulation of CNS microglial specific quiescent/anti-inflammatory markers (63) all evidence supporting a role of adiponectin to induce disease in children with MS. Finally, there has been evidence suggesting that obesity, through disruption of TH17/Treg balance, may alter the gut microbiome resulting in dysregulation of the intestinal immune response (65).…”

“…Obesity has also been associated with IL-6 dependent TH17 production which has been shown to exacerbate EAE in mice (62). Another adipokine, adiponectin, has also been implicated in the pathogenesis of MS (63). One study found elevated levels of leptin and fatty acid binding protein-4 as well as reduced adiponectin in boys and girls with MS compared to age and sex-matched controls (64).…”

Pediatric multiple sclerosis: The 2022 ECTRIMS lecture

“…Moreover, serum from POMS patients induced an adiponectin-driven pro-inflammatory response characterized by activation of CD4 and CD8 T cells as well as reduced microglial senescence. 30 POMS risk is also increased by exposure to secondhand smoke during childhood. 31 In adults with MS, smoking has also been linked to worse outcomes, including greater disability.…”

“…Moreover, serum from POMS patients induced an adiponectin-driven pro-inflammatory response characterized by activation of CD4 and CD8 T cells as well as reduced microglial senescence. 30…”