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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02312

Setmelanotide, a novel, selective melanocortin receptor-4 agonist exerts anti-inflammatory actions in astrocytes and promotes an anti-inflammatory macrophage phenotype

 Alwin Kamermans1, 2, 3, Tom Verhoeven1, 2, 3, Bert van het Hof1, 2, 3, Lauri H. Borghuis1, 2, 3,  Maarten E. Witte1, 2, 3,  Jack Van Horssen1, 2, 3,  Helga E. De Vries1, 2, 3 and  Merel Rijnsburger1, 2, 3*
  • 1Department of Molecular Cell Biology and Immunology, VU University Medical Center, Netherlands
  • 2MS Center Amsterdam, Medical Center, VU University Amsterdam, Netherlands
  • 3Amsterdam Neuroscience, Medical Center, VU University Amsterdam, Netherlands

To date, available treatment strategies for multiple sclerosis (MS) are ineffective in preventing or reversing progressive neurologic deterioration, creating a high and unmet medical need. One potential way to fight MS may be by limiting the detrimental effects of reactive astrocytes, a key pathological hallmark for disease progression.
One class of compounds that may exert beneficial effects via astrocytes are melanocortin receptor (MCR) agonists. Among the MCR, MC4R is most abundantly expressed in the CNS and several rodent studies have described that MC4R is – besides neurons - expressed by astrocytes. Activation of MC4R in astrocytes has shown to have potent anti-inflammatory as well as neuroprotective effects in vitro, suggesting that this could be a potential target to ameliorate ongoing inflammation and neurodegeneration in MS. In this study, we set out to investigate human MC4R expression and analyze its downstream effects. We identified MC4R mRNA and protein to be expressed on astrocytes and observed increased astrocytic MC4R expression in active MS lesions. Furthermore we show that the novel, highly selective MC4R agonist setmelanotide ameliorates the reactive phenotype in astrocytes in vitro and markedly induced interleukin -6 and -11 production, possibly through enhanced cAMP response element-binding protein (CREB) phosphorylation. Notably, stimulation of human macrophages with medium from astrocytes that were exposed to setmelanotide, skewed macrophages towards an anti-inflammatory phenotype. Taken together, these findings suggest that targeting MC4R on astrocytes might be a novel therapeutic strategy to halt inflammation-associated neurodegeneration in MS.

Keywords: Multiple Sclerosis, Inflammation, melanocortin, melanocortin 4 receptor (MC4R), astrocyte, macrophage

Received: 14 Jun 2019; Accepted: 12 Sep 2019.

Copyright: © 2019 Kamermans, Verhoeven, van het Hof, Borghuis, Witte, Van Horssen, De Vries and Rijnsburger. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Merel Rijnsburger, Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, 1081, Netherlands, m.rijnsburger@vumc.nl