BRAP Homologue Deficiency Exacerbates Airway Inflammation in Mouse Models of Experimental Asthma-Like Disease

Bronchial epithelial cells (BECs) play a critical role in asthma pathogenesis through structural and functional alterations that contribute to disease severity. Bombesin receptor-activated protein (BRAP), encoded by the human C6orf89 gene, shares 83% identity with its mouse homologue encoded by BC004004. Both proteins have been identified in bronchial epithelial cells, and our previous studies found that BRAP overexpression alters the biological behaviour of cultured human bronchial epithelial cells, suggesting a potential role in regulating immune homeostasis in the respiratory tract. In this study, we used BC004004 knockout (BC004004^-/-) mice, which lack expression of the BRAP homologue, to establish ovalbumin (OVA)-induced or house dust mite (HDM)-induced asthma models. Following OVA or HDM challenge, BC004004^-/- mice exhibited exacerbated airway inflammation compared with wild-type controls, characterised by increased mucus production in the airway lumen, enhanced shedding of bronchial epithelial cells, and more pronounced infiltration of inflammatory cells surrounding the bronchi and bronchioles. Meanwhile, the levels of Th2 cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) were significantly elevated in BC004004^-/- mice after allergen exposure. In addition, serum levels of thymic stromal lymphopoietin (TSLP), a key epithelial-derived mediator of type 2 immune responses, were increased in BC004004^-/- mice following OVA or HDM challenge. In cultured immortalised human bronchial epithelial cells, TSLP release was upregulated by BRAP knockdown and suppressed by BRAP overexpression. Further analysis revealed that BRAP homologue deficiency resulted in reduced E-cadherin expression in asthmatic lung tissues. Together with the enhanced epithelial shedding observed in the lungs of allergen-challenged BC004004^-/- mice, these findings suggest that loss of BRAP homologue compromises epithelial barrier integrity. The enhanced disruption of epithelial barrier integrity in BC004004^-/- mice may promote increased TSLP release from airway epithelial cells, thereby contributing to the exacerbation of allergic inflammation and asthma pathogenesis. Collectively, these results indicate a role for BRAP in maintaining epithelial barrier function during allergic asthma.