ST2L Negatively Regulates Therapeutic TLR9 Activation in Asthma.

Immunology;Asthma;TLR9;ST2L;Aspergillus;Dendritic Cells;Microbiology and Immunology;Pathology;Health Sciences;Immunology

Ramaprakash, HemanthStandiford, Theodore J. ;

University of Michigan

关键词: Immunology;    Asthma;    TLR9;    ST2L;    Aspergillus;    Dendritic Cells;    Microbiology and Immunology;    Pathology;    Health Sciences;    Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/77790/hprakash_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Asthma is a major cause of morbidity worldwide and this disease continues to increase in severity and prevalence, especially in the developed world.Clinical studies involving CpG-ODN therapy in asthmatics have identified that CpG-ODN drives a Th1 response, but does not inhibit airway hyperresponsiveness (AHR) in clinical asthma.In a murine fungal model of asthma, TLR9 plays a critical role in antifungal responses and is necessary for effective CpG-ODN therapy of asthma.Our experimental investigations have demonstrated that CpG-ODN administration promotes elevations in IL-12 levels, but no decrease in AHR in fungal asthma.These findings have provided a model in which to explore the mechanisms that inhibit CpG-ODN therapy from having efficacy for asthma.The IL-1R family protein ST2L is the receptor for IL-33.ST2L is present on immune and non-immune cells particularly during Th2-mediated disease.Recently, ST2L was identified as a negative regulator of MyD88-mediated TLR signaling.We have observed through immunohistochemical staining that ST2L progressively increases in the lung in asthmatic C57BL/6 mice along with the levels of TLR9.Herein, we have investigated whether blockade of ST2L enhances the therapeutic properties of CpG-ODN in a chronic fungal model of asthma.In our asthma model, C57BL/6 mice are sensitized to soluble A. fumigatus antigens and challenged with live A. fumigatus conidia.We investigated our model of fungal asthma first in TLR9+/+ and TLR9-/- mice followed by site directed therapy through either the intranasal (IN) or systemic intraperitoneal (IP) route from days 14 to 28-post conidia challenge.Additionally, mice were treated with an antibody targeting ST2L, IP CpG, IgG control, or combinations of the antibodies with CpG from days 14 to 28-post conidia challenge.Airway responses were attenuated in mice treated with α-ST2L+CpG, but not α-ST2L alone or CpG alone.In vitro studies with bone marrow derived DCs showed that targeting ST2L with CpG therapy decreased pSTAT3 levels in these cells, while increasing IL-12p70 levels.Together these data demonstrate that systemic TLR9 activation can reverse all features of chronic fungal asthma when delivered concomitantly with an anti-ST2L antibody.These data suggest that ST2L blockade enhances CpG-mediated therapeutic effects in asthma.