The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

Immunity. 2016 Feb 16;44(2):246-58. doi: 10.1016/j.immuni.2016.01.008. Epub 2016 Feb 9.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Dermatophagoides / immunology
  • Antigens, Protozoan / immunology
  • Asthma / immunology*
  • Blood Platelets / immunology*
  • Cell Differentiation
  • Cells, Cultured
  • Cytokines / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation
  • Humans
  • Inflammation / immunology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Leishmania major / immunology*
  • Leishmaniasis, Cutaneous / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Animal
  • Pyroglyphidae
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Th2 Cells / immunology*
  • Wnt Proteins / antagonists & inhibitors*


  • Antigens, Dermatophagoides
  • Antigens, Protozoan
  • Cytokines
  • Dkk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Wnt Proteins
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases