Related Experiment Videos
Experimental atopic dermatitis depends on IL-33R signaling via MyD88 in dendritic cells
Changwei Li1,2, Isabelle Maillet1, Claire Mackowiak1
1Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS and University of Orleans, F-45071 Orleans-Cedex 2, France.
Abstract:
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.
Insights
MyD88 signaling in dendritic cells is crucial for atopic dermatitis (AD) development. Interleukin-33 (IL-33) signaling via ST2 is essential, suggesting IL-33/IL-33R as a potential therapeutic target for AD.
Area of Science:
- Immunology
- Dermatology
- Molecular Biology
Background:
- Atopic dermatitis (AD) is a chronic inflammatory skin condition.
- MyD88 signaling pathways are implicated in inflammatory responses.
- The role of IL-1 family cytokines in experimental AD requires further elucidation.
Purpose of the Study:
- To investigate the role of MyD88 signaling in experimental atopic dermatitis (AD) induced by MC903.
- To identify key Interleukin-1 (IL-1) family cytokines involved in MC903-induced AD pathogenesis.
- To explore the specific cellular compartments where MyD88 signaling is critical for AD development.
Main Methods:
- Utilized MyD88 knockout (MyD88-/-) mice to assess the impact on MC903-induced AD.
- Examined the expression of IL-1 family cytokines in the context of experimental AD.
- Employed knockout mice for specific IL-1 family members (IL-33, ST2, IL-1α, IL-1β, IL-36R, IL-36Ra) to determine their necessity.
- Generated dendritic cell (DC)-specific MyD88 knockout mice (CD11c-cre × MyD88-floxed) to pinpoint MyD88's role in DCs.
Main Results:
- MC903-induced AD symptoms and inflammation were significantly reduced in MyD88-/- mice.
- IL-33 and its receptor ST2 were identified as critical mediators, with IL-33-/- and ST2-/- mice showing reduced AD.
- MyD88 signaling within dendritic cells was essential, as DC-specific MyD88 deficiency drastically reduced AD inflammation.
- IL-1α, IL-1β, IL-36 cytokines showed less significant roles in this AD model.
Conclusions:
- MyD88 signaling in dendritic cells plays a critical role in the pathogenesis of experimental atopic dermatitis.
- Interleukin-33 (IL-33) signaling through its receptor ST2 is essential for MC903-induced AD.
- Targeting the IL-33/ST2 pathway presents a potential therapeutic strategy for atopic dermatitis.