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

Wook Jin Chae, Allison K. Ehrlich, Pamela Y. Chan, Alexandra M. Teixeira, Octavian Henegariu, Liming Hao, Jae Hun Shin, Jong Hyun Park, Wai Ho Tang, Sang Taek Kim, Stephen E. Maher, Karen Goldsmith-Pestana, Peiying Shan, John Hwa, Patty J. Lee, Diane S. Krause, Carla V. Rothlin, Diane McMahon-Pratt, Alfred L.M. Bothwell

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

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-(Dkk-1) upon allergen challenge or non-healing parasitic infection. The increased circulating amounts of Dkk-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-was primarily from platelets, and the increase of Dkk-resulted in formation of leukocyte-platelet aggregates (LPA) that facilitated leukocyte infiltration to the affected tissue. Functional inhibition of Dkk-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-from thrombocytes is an important regulator of leukocyte infiltration and polarization of immune responses in pathological type 2 cell-mediated inflammation.

Original languageEnglish
Pages (from-to)246-258
Number of pages13
JournalImmunity
Volume44
Issue number2
DOIs
Publication statusPublished - 2016 Feb 16

Bibliographical note

Funding Information:
We thank Gouzel Tokmulina and Tom Taylor for cell sorting and Christine Cote for technical help in AMNIS operation. This work was supported by NIH 1R21AI107957-01 and NIH 1R01CA168670-01 (both awarded to A.L.M.B.), AI093775 (D.M.-P.), R01 AI089824 (C.V.R.), and T32 AI007019 (P.Y.C.). AMNIS work was supported by the Shared Instrument Grant (1-S10-RR-026526-01).

Funding Information:
We thank Gouzel Tokmulina and Tom Taylor for cell sorting and Christine Cote for technical help in AMNIS operation. This work was supported by NIH 1R21AI107957-01 and NIH 1R01CA168670-01 (both awarded to A.L.M.B.), AI093775 (D.M.-P.), R01 AI089824 (C.V.R.), and T32 AI007019 (P.Y.C.). AMNIS work was supported by the Shared Instrument Grant (1-S10-RR-026526-01).

Publisher Copyright:
© 2016 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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