Macrophage-derived progranulin produced in the early sensitization period plays an important role in the development of allergen induced TH2 dominant airway inflammation = 알레르기성 기도 염증에서 대식세포 유래 progranulin 의 역할

다국어 초록 (Multilingual Abstract)

Heterogeneity of asthma in its pathophysiology and clinical phenotypes has led to the development of new treatment strategies in which a biologic agent targets a key pathway of a certain inflammatory cascade. Progranulin, as a new biomarker in asthma was suggested based on a series of studies that demonstrated its anti-inflammatory role in animal models of acute lung injury and emphysema, also on a clinical study of asthma that showed its association with airway obstruction and blood neutrophilia. The specific function of progranulin and its mechanism of action in asthma is unknown, therefore, we aimed to investigate its immunologic role in asthma. To evaluate the effect of allergen exposure to progranulin in the airway, house dust mite (HDM) extract was administered intranasally in a mouse model and we found increased progranulin levels along with type 1 and 2 cytokines in bronchoalveolar lavage (BAL) fluid. The source of progranulin was alveolar macrophages. The effect of macrophage-derived progranulin on airway was evaluated with intranasal treatment of recombinant progranulin in mice and the results showed increased alveolar macrophages, neutrophils and type 2 cytokines, and the cytokines were produced from natural killer T (NKT) cells and lung epithelial cells. In the model of macrophage-derived progranulin deficient mice, HDM exposure did not induce innate and adaptive immune responses, and these responses were restored by progranulin supplement in the sensitization period. Also, the deficiency in macrophage-derived progranulin resulted in markedly decreased inflammation in histologic analysis of lung tissue after HDM exposure. Thus, the presence of macrophage-derived progranulin in the airway was shown to be important for the generation of T helper cell type 2 (TH2) immune response to HDM allergen exposure.

목차 (Table of Contents)

• Abstract i
• Table of contents iii
• Table of figures vi
• 1. Introduction 1
• 1.1 Asthma, a heterogeneous disease of the airway 1
• 1.2. Pathobiology of asthma 3
• 1.3. New biologic agents for asthma 8
• 1.4. Progranulin 9
• 1.4.1. The functions of progranulin 9
• 1.4.2. Association between progranulin and respiratory diseases, including asthma 11
• 1.5. Possible role of progranulin in allergic airway inflammation 12
• 2. Materials and methods 13
• 2.1. Mice 13
• 2.2. Materials for stimulation of cell line or mice 13
• 2.3. Culture and stimulation of mouse alveolar macrophage, epithelial cell and NKT cell 14
• 2.4. Establishment of airway inflammation in animal model 14
• 2.5. Processing of BAL fluid, serum isolation and peritoneal fluid 17
• 2.6. Single cell isolation from lung tissues and regional lymph nodes 17
• 2.7. Evaluation of immune responses of the single cells obtained from lungs and regional lymph nodes 18
• 2.8. Measurement of cytokines in BAL fluid/culture supernatant and immunoglobulin in serum 18
• 2.9. Evaluation of lung histology 19
• 2.10. Statistical analysis 19
• 3. Results 20
• 3.1. Airway inflammation and production of cytokines and progranulin was induced by HDM allergen exposure 20
• 3.2. Alveolar macrophage was the source of progranulin production at HDM allergen exposure 23
• 3.3. Intranasal treatment of recombinant progranulin increased airway inflammation 25
• 3.4. Progranulin induced production of type 2 cytokines from NKT and lung epithelial cells 29
• 3.5. Effect of macrophage-derived progranulin on the development of innate immune response induced by HDM allergen stimulation 32
• 3.6. Effect of macrophage-derived progranulin on the development of adaptive immunity induced by HDM allergen stimulation 38
• 3.7. Progranulin supplement in the sensitization period restored down-regulated Der p specific airway inflammation in macrophage-derived progranulin deficient mice 46
• 3.8. Effect of the progranulin on the development of adaptive immune response in conventional alum model 53
• 3.9. Effect of OVA/alum stimulation on the induction of progranulin in peritoneal cavity 60
• 4. Discussion 62
• 5. Conclusion 72
• 6. References 73
• 7. Korean abstract 86