Innate immune mechanisms of chronic airways disease

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The human respiratory tract is exposed to environmental irritants on a daily basis. The innate immune system is composed of different cellular components including the resident airway epithelium and macrophages and acts as the first line of defense to protect the lung against inhaled irritants. Activation of innate immune pathways is associated with the release of different mediators like cytokines, chemokines, lipid mediators and complement factors to mediate the recruitment of different immune cells into the airway lumen. The role of the innate immune system in chronic airways disease is currently a major area of research in the field and the focus of this thesis. RAGE and TLR4 are two major innate immune receptors implicated in the pathogenesis of asthma and COPD. We used TLR4, RAGE and TLR4/RAGE deficient mice to study the individual and combined role of these receptors in the airway response to acute cigarette-smoke exposure. We found that RAGE but not TLR4 deficiency protected against cigarette-smoke induced neutrophilic airway inflammation, mediator release and airway hyperreactivity (AHR). Interestingly, TLR4 deficiency exacerbated AHR. Together these findings, suggest that RAGE rather than TLR4 should be pursued as a therapeutic target in COPD. In contrast to our findings above however, we found that dual inhibition of TLR4/RAGE signaling, but not individual inhibition of these receptor pathways, protects against corticosteroid-resistant airway neutrophilia and AHR in an experimental model of severe asthma. Also, by performing a global phosphoproteomics analysis of lung tissue samples, we identified novel signaling pathways activated down-stream of TLR4/RAGE ligation in severe experimental asthma. We also investigated the role of macrophage migration inhibitory factor (MIF) in severe asthma. We demonstrated increased expression of MIF, S100A8/A9 and TLR4, and reduced expression of annexin A1 (ANXA1) in subjects with predominant airway neutrophilic inflammation. We also demonstrated that MIF inhibition protects against corticosteroid-resistant neutrophilic inflammation and airway hyperreactivity, and restores corticosteroid sensitivity in an experiental mouse model of severe asthma. Beneficial effects of MIF inhibition were associated with inhibition of S100A8 and CCL11 protein in the bronchoalveolar lavage fluid and reduced proteolytic cleavage of ANXA1. While ISO-1 had no effect on the secretion of pro-neutrophilic mediators, including IL-1 family cytokines, it did render these pathways sensitive to inhibition by dexamethasone. Finally, we identified a role for FhHDM-1, an immunomodulatory peptide derived from liver fluke 𝘍𝘢𝘴𝘤𝘪𝘰𝘭𝘢 𝘩𝘦𝘱𝘢𝘵𝘪𝘤𝘢 as a novel therapeutic treatment for asthma. Administration of FhHDM-1 protected against eosinophilic and neutrophilic inflammation, mucus secretion and AHR in a mouse model of house-dust mite induced asthma. In summary, the studies in this thesis have uncovered new molecular mechanisms of innate immune activation associated with the inception and progression of COPD and severe asthma, and have identified a novel helminth-based therapy for the treatment of asthma.
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