Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Neutrophilic asthma is a subtype of severe asthma, which has no safe and effective therapy. There is an unmet need to delineate the mechanism of neutrophilic asthma and develop targeted and effective therapies. Host cell-derived DNA is present in the extracellular fluid and serum. DNA represents a danger signal (danger- associate molecular pattern-DAMP) for host cells. Recent studies suggest an important role for extracellular DNA in mediating virus-induced asthma exacerbation. We present robust preliminary data demonstrating increased levels of extracellular DNA, the DNA sensor IFI16 (Interferon-gamma induced protein-16) and the DNA-IFI16 pathway-driven cytokines/chemokines in the airways from neutrophilic asthma. We developed a mouse model of asthma where DNA induces neutrophilic inflammation in the context of an IL10-constrained inflamed airway milieu. This phenotype requires the participation of the IFI16 signaling adapter STING. Based upon these novel preliminary results we hypothesize that extracellular DNA induces neutrophilic asthma through the IFI16-STING pathway in the presence of select IL10-suppressive TNFSFs. Neutrophil extracellular traps generate DNA, which establishes a self-perpetuated mechanism of neutrophilic asthma. Under Aim 1 we will examine the relevance of extracellular DNA for human neutrophilic asthma. We will study the generation of airway extracellular DNA, activation of IFI16 and IL10-suppressive TNFSFs—TNF and OX40L and their pathophysiological consequences in the airways. We will study bronchoalveolar lavage (BAL), bronchial epithelial cells and biopsy specimens from 3 study groups: 1) Neutrophilic (with and without eosinophilic) asthma; 2) Non-neutrophilic (with and without eosinophilic) asthma; and 3) Disease controls. We will delineate the function and importance of IFI16 for proneutrophilic biomolecules in a reductionist model in DNA-treated airway macrophages and blood monocytes. Under Aim 2 we will study the mechanism of extracellular DNA- induced neutrophilic asthma in mice. We will elucidate the role of IL10 and TNFSFs (TNF and OX40L) in switching the DNA-induced defensive program to a neutrophilic inflammation program in mouse airways. We will establish the role of IFI204 (the mouse IFI16 ortholog) and STING in neutrophilic inflammation. We will study the effect of removal of extracellular DNA on persistence of neutrophilic asthma in mice. This project is important because it uncovers a novel DNA-IFI16-STING mechanism of neutrophilic asthma and assesses the therapeutic benefits of DNA and STING inhibitors, and DNA scavengers in a preclinical study.
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