Role of breast regression protein (BRP-39) in Respiratory Syncytial Virus-induced airway inflammation

Abstract

Chitinase 3-like 1 (CHI3L1), has been shown to be necessary for optimal allergen sensitization and Th2 inflammation in various chronic inflammatory diseases including asthma. However, the role of CHI3L1 in airway inflammation induced by respiratory viruses has not been proved yet. The purpose of this study is to determine the relationship between breast regression protein-39 (BRP-39), a mouse chitinase 3-like 1 protein, and airway inflammation followed by respiratory syncytial virus (RSV) infection. In this study, C57BL/6 mice and C57BL/6-background BRP-39 null mice were used. Mice were inoculated with live A2-strain RSV and control PBS. A methacholine challenge test to measure airway resistance worked on day 7 after inoculation. Bronchoalveolar lavage fluid (BALF) samples were obtained and lung specimens were also harvested on day 7 after inoculation to assess lung inflammation, cytokine expression, and BRP-39 production. BRP-39 expression was evaluated by ELISA. RSV loads were assessed by culture and by real-time polymerase chain reaction (PCR). Histological evaluations of H&E and PAS staining were used to evaluate inflammation and tissue remodeling. Expression of BRP-39 in BALF and lung lysates was significantly increased in wild-type (WT) mice after RSV infection, but was not observed in BRP-39 null mice. Inflammatory changes induced by RSV infection were less in BRP-39-/- mice rather than in WT mice. In WT mice, RSV infection caused loss of body weight and a significant increase in total cells, macrophages, neutrophils, and eosinophils in BALF. Exaggerated AHR was also noted in WT mice after RSV infection. BRP-39-/- mice, however, showed decreased responses in each of these parameters. Between RSV infection groups, histological tissue inflammation was also decreased in BRP-39-/- mice. Expression of Th2 cytokines in the lungs was increased in RSV-infected mice. IL-13 was the most prominent cytokine changed by RSV infection in this study. BRP-39 also regulated M2 macrophage activation in RSV-infected mice. To investigate the therapeutic effect of anti-CHI3L1 antibody in RSV infection, anti-CHI3L1 was administered intraperitoneally to RSV-infected WT mice. Mice given anti-CHI3L1 treatment showed less inflammatory changes compared to WT RSV mice. Expression of BRP-39 and Th2 cytokines were also significantly decreased in mice treated with anti-CHI3L1. When measuring the human homologue of CHI3L1, YKL-40, in nasopharyngeal aspirates (NPA) from hospitalized children presenting with acute respiratory symptoms, YKL-40 and IL-13 levels were significantly higher in children with RSV infection than in control subjects. In addition, YKL-40 levels were positively correlated with symptom scores in patients and with IL-13 levels in NPA. RSV-related respiratory illness has been a leading cause of hospitalization in young childhood. RSV is also known as a significant risk factor for asthma that extends into adolescence and adults, and its mechanism is still under investigation. In this study, expression of BRP-39 increased by RSV infection in mice. And inflammatory changes and AHR induced by RSV were decreased in BRP-39 null mice and in anti-CHI3L1-treated mice. These findings suggest that CHI3L1 could contribute to airway inflammation induced by RSV infection in mice and that BRP-39 could be a potential therapeutic target for attenuating Th2-associated immunopathology during RSV infection.