The Role of Mfge8 and Apoptotic Cell Clearance in Regulating Asthma Severity

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DESCRIPTION (provided by applicant): Asthma is a chronic immunologically mediated disease characterized by an overactive immune response to antigens, inflammation and airway obstruction. The incidence of asthma is increasing globally. Current therapies primarily target symptomatic management of airway obstruction and global suppression of the immune system. More specific therapies targeting the immune system will be of great benefit. Milk fat globule epidermal growth factor like 8 (Mfge8) is a soluble glycoprotein that binds and targets apoptotic cells for removal. Phagocytes secrete anti-inflammatory cytokines with key immune dampening roles in asthma after engulfing apoptotic cells by a Mfge8 dependent mechanism. During an acute asthmatic flare, inflammatory cells are recruited into the lung and undergo apoptosis and apoptotic cell clearance. In asthmatic patients, efficient apoptotic cell clearance is associated with less severe disease and recovery from an acute flare suggesting that the process of apoptotic cell clearance promotes the resolution of asthma exacerbations. The overall objective of this proposal is to evaluate the relationship of Mfge8-mediated apoptotic cell clearance in modulating asthma severity. We hypothesize that Mfge8-mediated apoptotic cell clearance of inflammatory cells dampens the asthmatic response through induction of anti-inflammatory signaling. This hypothesis will be explored through 2 specific aims. The first specific aim is to determine whether Mfge8 mediates apoptotic cell clearance after allergen challenge in the lung and whether impaired apoptotic cell clearance exacerbates experimental asthma. The second specific aim is to determine whether Mfge8 regulates the severity of asthma through modulation of the adaptive immune response. Our experimental approach involves evaluating the response of mice deficient in Mfge8 to an ovalbumin induced model of experimental asthma. We will test whether Mfge8 deficiency leads to impaired apoptotic cell clearance in vivo after asthma induction by multiple methods including quantification of the number of apoptotic cells on tissue sections, quantification of alveolar macrophages phagocytic capacity, and evaluation of whether the addition of exogenous apoptotic cells regulates the severity of the response to allergen challenge. We will also evaluate differences in the adaptive response to allergen challenge with Mfge8 deficiency. We will do this by isolating and characterizing the cytokine and lymphocyte profile from the bronchoalveolar lavage, lung parenchyma, and thoracic lymph nodes of Mfge8 deficient and control mice. These studies have the potential to identify both a novel inhibitory pathway and a new candidate molecule that may be targeted as a disease modifying agents for the treatment of allergic diseases. PUBLIC HEALTH RELEVANCE: Asthma is a chronic allergic/inflammatory disease of the lung with increasing prevalence and incomplete treatment options. Research aimed at discovering the mechanisms that lead to asthma will provide new therapeutic options. The goals of this project are work out the mechanisms by which the protein Mfge8 regulates asthma severity and to identify new therapeutic targets for the treatment of allergic diseases.