| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 106 === Allergic airway inflammation is a TH2-mediated disorder in which sensitized individuals develop eosinophilic airway inflammation, mucus hypersecretion and airway hyperresponsiveness in response to inhaled aeroallergens. According to a published record, the incidence of pediatric asthma has increased for more than 10 times in the past few decades in Taiwan and the cost of care is more than 11.3 billion per year in USA. Thus understanding the pathogenesis of allergic asthma that will help us to develop preventative or alternative therapeutics for allergic airway inflammation diseases, such as asthma has always been an important task.
In this thesis, I aimed to investigate the functional roles of two independent molecules, CXCR7 and TRIM37 in allergic airway inflammation.
CXCR7
Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signaling or modulated CXCR4-mediated signaling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral-delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. We found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12-mediated signaling through β-arrestin in airway epithelial cells. Thus, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation. Unfortunately, small molecules CCX771 known to be an antagonist of CXCR7 failed to have any therapeutic effect on either acute or chronic allergic airway inflammation.
TRIM37
TRIM37 is the only member of Tripartite motif (TRIM) family protein that contains TRAF domain, endowing it being able to interact with protein containing TRAF domain. Studies indicated that TRIM37 might involve in regulating PRR-, TNFR- and cytokine -mediated signaling pathways suggesting its important role in regulating immune responses. However, whether TRIM37 involve in the development of allergic airway inflammation remains to be examined. In my studies, we idnetified that TRIM37 can be detected in the leukocytes including T cell, dendritic cells (DCs), and macrophages. When using immunohistochemistry staining of lung tissues from naïve and allergen-induced inflamed mice, positive staining of TRIM37 was observed in the infiltrated leukocytes. Interestingly, the expression of TRIM37 can be detected in airway epithelial cells, and was further augmented when lung was inflamed. An experiment using a murine asthma model, in which the Trim37 were knocked-down by intratracheally delivering lentivirus carrying Trim37 shRNA into the sensitized mice before challenge showed that knockdown of TRIM37 expression in lung diminished cardinal features of asthma. However, when Trim37 in the lung were knocked-down before sensitization showed augmented airway inflammation and TH2-type cytokine production, implicating its complexed role in regulating allergic airway inflammation. In parallel, I also identified that when lesser Trim37 expression in T cells, the T-bet expression in TH1 was reduced, whereas GATA-3 expression in TH2 cells was increased, indicating TRIM37 in hematopoietic and non-hematopoietic compartments might both have functional role in regulating allergic airway inflammation.
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