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Published on: July 7, 2017
Targeting ST2L potentiates CpG-mediated therapeutic effects in a chronic fungal asthma model
Hemanth Ramaprakash1, Takehiko Shibata, Karen E Duffy
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Abstract:
IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.
Insights
Blocking ST2L enhances CpG therapy for fungal asthma. Combining anti-ST2L monoclonal antibody with CpG significantly reduced asthma symptoms and pathology in a mouse model.
Area of Science:
- Immunology
- Allergy and Asthma Research
- Infectious Disease
Background:
- Interleukin-33 (IL-33) and its receptor ST2 (suppression of tumorigenicity 2) are elevated in asthma.
- ST2L is implicated in modulating immune responses during allergic inflammation.
- The role of ST2L in the efficacy of CpG-based asthma therapies remains unclear.
Purpose of the Study:
- To investigate whether ST2L impairs the therapeutic effects of CpG in a fungal model of asthma.
- To evaluate the combined therapeutic potential of ST2L blockade and CpG administration.
Main Methods:
- C57BL/6 mice were sensitized and challenged with Aspergillus fumigatus to model fungal asthma.
- Mice received treatments including IgG, anti-ST2L monoclonal antibody (mAb), CpG, or combinations thereof.
- Lung ST2L and toll-like receptor 9 (TLR9) expression, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were assessed.
Main Results:
- Lung ST2L and TLR9 expression increased with fungal asthma development.
- Therapeutic blockade of ST2L with an mAb alone did not significantly affect asthma severity.
- Combination therapy with anti-ST2L mAb and CpG markedly reduced airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention.
- Combination therapy elevated CXCL9 levels and enhanced dendritic cell IL-12p70 production in response to CpG.
Conclusions:
- ST2L blockade enhances the therapeutic efficacy of CpG in experimental fungal asthma.
- Targeting ST2L in conjunction with CpG offers a promising strategy for managing allergic airway inflammation.
- This combination therapy may represent a novel approach to treating fungal-induced asthma.
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