title: The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation.
abstract: Exposure to a plethora of environmental challenges commonly triggers pathological type 2 cell-mediated inflammation. Here we report the pathological role of the Wnt antagonist Dickkopf-1 (Dkk-1) upon allergen challenge or non-healing parasitic infection. The increased circulating amounts of Dkk-1 polarized T cells to T helper 2 (Th2) cells, stimulating a marked simultaneous induction of the transcription factors c-Maf and Gata-3, mediated by the kinases p38 MAPK and SGK-1, resulting in Th2 cell cytokine production. Circulating Dkk-1 was primarily from platelets, and the increase of Dkk-1 resulted in formation of leukocyte-platelet aggregates (LPA) that facilitated leukocyte infiltration to the affected tissue. Functional inhibition of Dkk-1 impaired Th2 cell cytokine production and leukocyte infiltration, protecting mice from house dust mite (HDM)-induced asthma or Leishmania major infection. These results highlight that Dkk-1 from thrombocytes is an important regulator of leukocyte infiltration and polarization of immune responses in pathological type 2 cell-mediated inflammation.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Wook-Jin
authors.initials: WJ
authors.lastname: Chae
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Allison K
authors.initials: AK
authors.lastname: Ehrlich
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Pamela Y
authors.initials: PY
authors.lastname: Chan
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Teixeira
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Octavian
authors.initials: O
authors.lastname: Henegariu
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Hao
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jae Hun
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jong-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Internal Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Wai Ho
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Department of Rheumatology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Sang-Taek
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Maher
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Goldsmith-Pestana
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Peiying
authors.initials: P
authors.lastname: Shan
authors.affiliation: Department of Internal Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hwa
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Diane S
authors.initials: DS
authors.lastname: Krause
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Carla V
authors.initials: CV
authors.lastname: Rothlin
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: alfred.bothwell@yale.edu.
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
mesh_terms: D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology; D001249:Asthma / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D039981:Pyroglyphidae; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*
chemical_list: D039741:Antigens, Dermatophagoides; D000953:Antigens, Protozoan; D016207:Cytokines; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases