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

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

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Department of Internal Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06520, USA.
6
Department of Rheumatology, Yale University School of Medicine, New Haven, CT 06520, USA.
7
Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
8
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.
9
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: alfred.bothwell@yale.edu.

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.

PMID:
26872695
PMCID:
PMC4758884
DOI:
10.1016/j.immuni.2016.01.008
[Indexed for MEDLINE]
Free PMC Article

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