The synthetic retinoid Am80 delays recovery in a model of multiple sclerosis by modulating myeloid-derived suppressor cell fate and viability.
Relapsing-remitting multiple sclerosis (RR-MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). It is characterized by relapsing phases with ongoing neurological affectation that are followed by a remitting period in which inflammatory events are controlled and the patients partially recover. Experimental Autoimmune Encephalomyelitis (EAE) is the animal model most often used to study the inflammatory component of MS. Several cell types are involved in controlling the immune response in EAE and immature myeloid-derived suppressor cells (MDSCs) have emerged as important actors in the immunomodulation that occurs in EAE due to their ability to suppress inflammatory responses by inducing T cell apoptosis. In this study, we assessed whether MDSC differentiation may have consequences on the clinical course of EAE by treating mice around the peak of the clinical course EAE with the MDSC-differentiating agent Am80, an analogue of retinoid acid. Am80 administration abrogates the immunomodulation that occurs in EAE mice through different MDSC-related mechanisms: i) induction of MDSC apoptosis; ii) polarization of MDSCs to mature subsets of myeloid cells (dendritic cells/macrophages/neutrophils); and iii) altering their immunosuppressor phenotype. Consequently, T cell density increases and their viability is promoted, delaying the animal's recovery. Therefore, our data point to MDSC behaviour as a crucial factor in facilitating the transition from the relapsing to the remission phase in EAE, which should be considered for future immune-related therapies for MS.
Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca "La Peraleda" s/n, E-45071 Toledo, Spain.
Verónica
V
Moliné-Velázquez
Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca "La Peraleda" s/n, E-45071 Toledo, Spain.
María Cristina
MC
Ortega
Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca "La Peraleda" s/n, E-45071 Toledo, Spain.
Virginia
V
Vila del Sol
Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca "La Peraleda" s/n, E-45071 Toledo, Spain.
Carolina
C
Melero-Jerez
Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca "La Peraleda" s/n, E-45071 Toledo, Spain.
Fernando
F
de Castro
Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca "La Peraleda" s/n, E-45071 Toledo, Spain. Electronic address: dclemente@sescam.jccm.es.
Diego
D
Clemente
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology* / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D000072482:Retinoic Acid Receptor alpha; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D001565:Benzoates; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; C061133:tamibarotene
Apoptosis; Dendritic cells; EAE; Immunomodulation; Lymphocyte; Neutrophil