title: Daphnetin Alleviates Experimental Autoimmune Encephalomyelitis via Regulating Dendritic Cell Activity.
abstract: Daphnetin, a coumarin derivative extracted from Daphne odora var. marginata, has been reported to have antiinflammatory and immunosuppressive properties. Our previous study indicated that it was able to remarkably suppress the neuroinflammation and suggested its potential application in treating neuroinflammatory diseases. Multiple sclerosis (MS), a Th cell-mediated autoimmune disease, is the most common inflammatory demyelinating disease of the central nervous system (CNS). We examined whether daphnetin treatment can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for MS.
  
  
  
  To assess the effect of daphnetin in neuroinflammatory diseases, the EAE mice were established and treated with daphnetin at 8 mg/kg for 28 days. The severity of neuroinflammation and demyelination in the spinal cords was examined histopathologically. Infiltration of CD4(+) T cells into the CNS was assessed by immunohistochemistry, and the cytokine production was determined by ELISA. Meanwhile, the effect of daphnetin on the activity of dendritic cells (DCs) was evaluated, as assessed by DCs' capability to express surface markers, secrete cytokines, and activate naïve CD4(+) T cells. Furthermore, we explored the molecular mechanisms whereby DAPH regulated DCs' activity and thereby CD4(+) T cell responses.
  
  
  
  The administration of daphnetin markedly alleviated the clinical symptoms of EAE and reduced the CNS inflammation and demyelination in experimental mice. Th1 and Th17 cell responses were profoundly repressed in daphnetin-treated EAE mice. Mechanistically, daphnetin treatment significantly repressed the activation, maturation, and antigen-presenting capability of DCs. NF-κB signaling was significantly reduced in daphnetin-treated DCs, along with a concomitant induction of heme oxygenase-1, a negative regulator of inflammatory signaling.
  
  
  
  Our findings for the first time demonstrate the property of daphnetin in regulating DCs' function and subsequently Th development. Given the low or absent toxicity associated with daphnetin, our data may suggest a novel safe and effective approach to control autoimmune neuroinflammation.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China.|Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Su-Feng
authors.initials: SF
authors.lastname: Jin
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China.
authors.forename: Yun-Man
authors.initials: YM
authors.lastname: Li
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, China.|Department of Microbiology and Immunology, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Li-Yun
authors.initials: LY
authors.lastname: Shi
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000166:cytology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014468:Umbelliferones / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B; D010446:Peptide Fragments; D014468:Umbelliferones; C445081:myelin oligodendrocyte glycoprotein (35-55); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C039952:daphnetin
keywords: Daphnetin; Dendritic cell; Experimental autoimmune encephalomyelitis; Th1; Th17