Oncostatin M protects against demyelination by inducing a protective microglial phenotype.
Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS), in which destruction of myelin sheaths leads to disturbed axonal conduction. Available MS therapies modulate the immune response, but are unable to prevent neurological decline. Therefore, great efforts are made to develop therapies that limit demyelination and axonal degeneration. Oncostatin M (OSM), a member of the interleukin (IL)-6 cytokine family, is produced in demyelinating lesions of MS patients and stimulates neuronal survival. In this study, we reveal that the OSM receptor (OSMR) was robustly upregulated on microglia/macrophages and astrocytes in the cuprizone-induced demyelination model. While OSMR deficiency led to aggravated demyelination, CNS-targeted OSM treatment largely prevented demyelination. OSM treatment increased IL-4 expression and induced polarization of myeloid cells towards an anti-inflammatory M2 phenotype in vivo. This study reveals a previously uncharacterized and protective role for OSM during demyelination, and indicates that OSM is a promising therapeutic candidate to limit CNS damage in demyelinating diseases including MS.
Department of Immunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Kris
K
Janssens
Department of Immunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Anurag
A
Maheshwari
Department of Neurosciences, Laboratory for Neurobiology and Gene Therapy, KU Leuven, Kapucijnenvoer 33, Leuven, Belgium.|Department of Neurosciences and Department of Pharmaceutical and Pharmacological Sciences, Leuven Viral Vector Core, KU Leuven, Kapucijnenvoer 33, Leuven, Belgium.
Chris
C
Van den Haute
Department of Neurosciences, Laboratory for Neurobiology and Gene Therapy, KU Leuven, Kapucijnenvoer 33, Leuven, Belgium.
Veerle
V
Baekelandt
Department of Immunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Piet
P
Stinissen
Department of Immunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Jerome J A
JJ
Hendriks
Department of Immunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Helena
H
Slaets
Department of Immunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Niels
N
Hellings
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002614:Chelating Agents / Q000633:toxicity; D003471:Cuprizone / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D053683:Oncostatin M / Q000494:pharmacology*; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D013997:Time Factors; D014161:Transduction, Genetic; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D002614:Chelating Agents; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D006131:Growth Inhibitors; D008840:Microfilament Proteins; D053681:Oncostatin M Receptor beta Subunit; C508349:Osmr protein, mouse; D053683:Oncostatin M; D003471:Cuprizone
demyelination; microglia; multiple sclerosis; oncostatin M