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Interleukin-33 primes mast cells for activation by IgG immune complexes
Shinjiro Kaieda1, Jun-Xia Wang, Ruslan Shnayder
1Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Plos One
|October 17, 2012
Summary
Interleukin-33 (IL-33) amplifies IgG immune complex-driven inflammation in arthritis by priming mast cells (MCs). This creates a positive feedback loop with synovial fibroblasts, highlighting IL-33
Area of Science:
- Immunology
- Cell Biology
- Inflammation Research
Background:
- Mast cells (MCs) are immune cells whose function is influenced by their microenvironment.
- Interleukin-33 (IL-33) is a cytokine that activates mast cells and regulates their phenotype.
- MCs contribute to experimental arthritis, and IL-33's role in this process is under investigation.
Purpose of the Study:
- To investigate if IL-33 promotes the activation of synovial mast cells by IgG immune complexes in murine K/BxN arthritis.
- To elucidate the mechanisms by which IL-33 influences mast cell activation and mediator production in arthritis.
Main Methods:
- Comparison of wild-type (WT) and IL-33 receptor ST2 knockout (ST2(-/-)) mice in a K/BxN arthritis model.
- Assessment of mast cell-dependent vascular permeability (flare) and arthritis severity.
- In vitro studies using bone marrow-derived mast cells (BMMCs) stimulated with IL-33 and IgG immune complexes.
- Analysis of gene expression and mediator production (IL-1β, CXCL2) in mast cells and synovial fibroblasts.
- Investigation of mast cell-fibroblast co-cultures and blocking antibody experiments.
Main Results:
- Mice lacking ST2 showed reduced MC-dependent vascular permeability and attenuated K/BxN arthritis.
- IL-33 directly induced cytokine release from BMMCs and enhanced FcγRIII-mediated production of IL-1β and CXCL2.
- This 'priming' effect involved increased mRNA accumulation, not altered Fcγ receptor expression.
- WT MCs, but not ST2(-/-) MCs, augmented fibroblast IL-33 expression, indicating a positive feedback loop.
- Antibodies against IL-33 blocked the priming effect.
Conclusions:
- IL-33 acts as a potent amplifier of IgG immune complex-mediated inflammation in arthritis.
- A novel IL-33/ST2-dependent positive feedback loop exists between mast cells and synovial fibroblasts.
- Targeting the IL-33-ST2 pathway may offer therapeutic strategies for inflammatory arthritis.
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