title: Topical Application of Fingolimod Perturbs Cutaneous Inflammation.
abstract: The prevalence of allergies, including rhinitis, eczema, and anaphylaxis, is rising dramatically worldwide. This increase is especially problematic in children who bear the greatest burden of this rising trend. Increasing evidence identifies neutrophils as primary perpetrators of the more severe and difficult to manage forms of inflammation. A newly recognized mechanism by which neutrophils are recruited during the early phase of histamine-induced inflammation involves the sphingosine kinase (SK)/sphingosine-1-phosphate axis. This study examines whether topical application of fingolimod, an established SK/sphingosine-1-phosphate antagonist already in clinical use to treat multiple sclerosis, may be repurposed to treat cutaneous inflammation. Using two mouse models of ear skin inflammation (histamine- and IgE-mediated passive cutaneous anaphylaxis) we topically applied fingolimod prophylactically, as well as after establishment of the inflammatory response, and examined ear swelling, SK activity, vascular permeability, leukocyte recruitment, and production of proinflammatory mediators. The present study reveals that when applied topically, fingolimod attenuates both immediate and late-phase responses to histamine with reduced extravasation of fluid, SK-1 activity, proinflammatory cytokine and chemokine production, and neutrophil influx and prevents ear swelling. Intravital microscopy demonstrates that histamine-induced neutrophil rolling and adhesion to the postcapillary venules in the mouse ears is significantly attenuated even after 24 h. More importantly, these effects are achievable even once inflammation is established. Translation into humans was also accomplished with epicutaneous application of fingolimod resolving histamine-induced and allergen-induced inflammatory reactions in forearm skin. Overall, this study demonstrates, to our knowledge for the first time, that fingolimod may be repurposed to treat cutaneous inflammation.
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia; School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia;
authors.forename: Wai Y
authors.initials: WY
authors.lastname: Sun
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia;
authors.forename: David P
authors.initials: DP
authors.lastname: Dimasi
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia;
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Pitman
authors.affiliation: School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia;
authors.forename: YiZhong
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia; Clinical Immunology Unit, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia; and Discipline of Pediatrics and Child Health, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Heddle
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia; School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia;
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia; School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia;
authors.forename: Michele A
authors.initials: MA
authors.lastname: Grimbaldeston
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia; School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia; claudine.bonder@unisa.edu.au.
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Bonder
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy*; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics; D012867:Skin / Q000187:drug effects* / Q000276:immunology; D000099157:Sphingosine Kinase
chemical_list: D016207:Cytokines; D000068876:Fingolimod Hydrochloride; D006632:Histamine; D007073:Immunoglobulin E; D018836:Inflammation Mediators; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase