title: Fetal inhibition of inflammation improves disease phenotypes in harlequin ichthyosis.
abstract: Harlequin ichthyosis (HI) is a severe skin disease which leads to neonatal death in ∼50% of cases. It is the result of mutations in ABCA12, a protein that transports lipids required to establish the protective skin barrier needed after birth. To better understand the life-threatening newborn HI phenotype, we analysed the developing epidermis for consequences of lipid dysregulation in mouse models. We observed a pro-inflammatory signature which was characterized by chemokine upregulation in embryonic skin which is distinct from that seen in other types of ichthyosis. Inflammation also persisted in grafted HI skin. To examine the contribution of inflammation to disease development, we overexpressed interleukin-37b to globally suppress fetal inflammation, observing considerable improvements in keratinocyte differentiation. These studies highlight inflammation as an unexpected contributor to HI disease development in utero, and suggest that inhibiting inflammation may reduce disease severity.
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Denny L
authors.initials: DL
authors.lastname: Cottle
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Gloria M A
authors.initials: GM
authors.lastname: Ursino
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Sally Chi Ieng
authors.initials: SC
authors.lastname: Ip
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Lynelle K
authors.initials: LK
authors.lastname: Jones
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Tia
authors.initials: T
authors.lastname: Ditommaso
authors.affiliation: Department of Anaesthetics, Saint Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia Department of Paediatric Intensive Care, The Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Hacking
authors.affiliation: Centre for Innate Immunity and Infectious Diseases.
authors.forename: Niamh E
authors.initials: NE
authors.lastname: Mangan
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Mellett
authors.affiliation: Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Katya J
authors.initials: KJ
authors.lastname: Henley
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Sviridov
authors.affiliation: The Ritchie Centre, MIMR-PHI Institute of Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Nold-Petry
authors.affiliation: The Ritchie Centre, MIMR-PHI Institute of Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia.
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Nold
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia and.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: Department of Biochemistry and Molecular Biology Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia ian.smyth@monash.edu.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Smyth
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004817:Epidermis / Q000196:embryology / Q000276:immunology; D005260:Female; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000196:embryology* / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012867:Skin / Q000196:embryology / Q000276:immunology
chemical_list: D018925:Chemokines; C508587:IL37 protein, human; D007375:Interleukin-1