Experimental atopic dermatitis depends on IL-33R signaling via MyD88 in dendritic cells

Cell Death Dis. 2017 Apr 6;8(4):e2735. doi: 10.1038/cddis.2017.90.


Atopic dermatitis (AD) is a chronic Th2 type inflammatory skin disorder. Here we report that MyD88 signaling is crucial in the pathogenesis of experimental AD induced by vitamin D3 analog MC903. The clinical signs and inflammation caused by MC903 are drastically reduced in MyD88-/- mice with diminished eosinophil, neutrophil infiltration and Th2 cytokine expression. The biological effect of interleukin-1 (IL-1) family members relies on MyD88 signaling. We observed a strong upregulation of IL-1 family cytokine expression, including IL-1α, IL-1β, IL-33, IL-18, IL-36α, IL-36β, IL-36γ and IL-36Ra. Therefore, we asked which cytokine of the IL-1 family would be essential for MC903-induced AD syndrome. We find a significant reduction of AD in IL-33-/- and IL-33R/ST2-/- mice, only a minor reduction in double IL-1αβ-/- mice and no difference in IL-36R-/- and IL-36Ra-/- mice. IL-33 is expressed in keratinocytes, and MyD88 signaling in dendritic cells (DCs) is crucial for AD development as inflammation was drastically reduced in DC-specific MyD88-/- mice (CD11c-cre × MyD88-floxed). Taken together, the data demonstrate a critical role of MyD88 in DCs and of IL-33 signaling via ST2 in MC903-induced AD. These data suggest that IL-33/IL-33R may be a therapeutic target of AD.

MeSH terms

  • Animals
  • Calcitriol / adverse effects
  • Calcitriol / analogs & derivatives
  • Calcitriol / pharmacology
  • Cytokines / genetics
  • Cytokines / immunology
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Dermatitis, Atopic / chemically induced
  • Dermatitis, Atopic / genetics
  • Dermatitis, Atopic / immunology*
  • Dermatitis, Atopic / pathology
  • Disease Models, Animal
  • Interleukin-1 Receptor-Like 1 Protein
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology*


  • Cytokines
  • Il1rl1 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin
  • calcipotriene
  • Calcitriol