알레르기성 기도 염증에서 대식세포 유래 progranulin 의 역할

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.