title: Liposomal encapsulation of glucocorticoids alters their mode of action in the treatment of experimental autoimmune encephalomyelitis.
abstract: Glucocorticoids (GCs) are widely used to treat acute relapses of multiple sclerosis (MS). In this study, we demonstrate that liposomal encapsulation augments the therapeutic potency of GCs as they ameliorate experimental autoimmune encephalomyelitis (EAE) to the same extent as free GC, but at strongly reduced dosage and application frequency. Importantly, this is accompanied by an altered mode of action. Unlike free GCs, which mainly target T lymphocytes during EAE therapy, liposomal GCs only marginally affect T cell apoptosis and function. In contrast, liposomal GCs efficiently repress proinflammatory macrophage functions and upregulate anti-inflammatory genes associated with the alternatively activated M2 phenotype. The GC receptor (GR) per se is indispensable for the therapeutic efficacy of liposomal GC. In contrast to free GCs, however, the individual deletion of the GR either in T cells or myeloid cells has little effect on the efficacy of liposomal GCs in the treatment of EAE. Only the combined deletion of the GR in both cellular compartments markedly compromises the therapeutic effect of liposomal GCs on disease progression. In conclusion, encapsulation of GC does not only enhance their efficacy in the treatment of EAE but also alters their target cell specificity and their mode of action compared with free GCs.
authors.affiliation: Department of Neuroimmunology, Institute for Multiple Sclerosis Research and the Hertie Foundation, University of Göttingen Medical School, 37073 Göttingen, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Schweingruber
authors.forename: Axel
authors.initials: A
authors.lastname: Haine
authors.forename: Karsten
authors.initials: K
authors.lastname: Tiede
authors.forename: Anna
authors.initials: A
authors.lastname: Karabinskaya
authors.forename: Jens
authors.initials: J
authors.lastname: van den Brandt
authors.forename: Simone
authors.initials: S
authors.lastname: Wüst
authors.forename: Josbert M
authors.initials: JM
authors.lastname: Metselaar
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage*; D007150:Immunohistochemistry; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011965:Receptors, Glucocorticoid / Q000172:deficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005938:Glucocorticoids; D008081:Liposomes; D011965:Receptors, Glucocorticoid