Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

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.

Interleukin-33 and the function of innate lymphoid cells

“…Although its roles in type 2 immunity are well-documented, the recent discovery of novel innate immune cells that respond strongly to this cytokine have emphasised and helped clarify important roles for IL-33 in parasitic infection [15,55] Fungal infection Increased IL-33 levels in the lungs of mice infected with Aspergillus fumigatus Attenuated allergic response to A. fumigatus with ST2L-blocking antibody in combination with a TLR9 agonist Alternaria alternata lung exposure induces ILC and airway inflammation [52,109] Asthma Increased production of IL-33 by alveolar macrophages in experimental pulmonary influenza Induction of M2 macrophages in experimental asthma, disease exacerbation Induction of ILCs and AHR in influenza infection Induction of ILC-mediated tissue repair in the lung via amphiregulin Increased levels in asthmatic lungs, correlating with disease severity Induction of eosinophilia IL-33 knockout mice have reduced airway inflammation in models of asthma [6,15,29,55,65,66,69] Cardiovascular Inhibits the formation of atherosclerotic plaques, protective type-2 immune responses Improves outcomes in models of myocardial infarction Protective effects in murine obesity-driven metabolic syndrome [6,39,[71][72][73] Arthritis Exacerbates inflammation in murine arthritis models and is reduced by anti-TNF therapy Elevated levels measured in sera and synovial fluid of rheumatoid arthritis patients Elevated sera levels respond to anti-TNF treatment and correlate with disease activity [40,76,84,85,110] Central nervous system Increased expression in activated glial cells Increased levels in experimental encephalitis Gene polymorphisms associated with Alzheimer's disease [88][89][90] Review Trends in Immunology August 2012, Vol. 33,No.…”

Crucial and Diverse Role of the Interleukin-33/ST2 Axis in Infectious Diseases

“…Targeting the IL-33/ST2 pathway could thus offer new therapeutic opportunities in this setting. Recently, in an asthma model with C57BL/6 mice sensitized with Aspergillus fumigatus, the blockade of the ST2 receptor with a specific monoclonal antibody improved the effect of treatment with CpG oligodeoxynucleotides, leading to a switch from a Th2 response to protective Th1 immunity through TLR9 activation (65).…”

IL-33 and Its Receptor ST2 after Inhaled Allergen Challenge in Allergic Asthmatics

“…Conversely, neutralization of IL-33 [15], or its receptor ST2L [16, 17], reduces airway inflammation, IgE levels, Th2 cytokine expression, goblet cell hyperplasia, and AHR. Furthermore, IL-33 mRNA expression has been found to be greater in epithelial cells of airway biopsies in asthmatics compared to healthy controls, with severe asthmatics expressing markedly greater levels as opposed to mild asthmatics [18-20].…”