Clara cell 16 KDa protein mitigates house dust mite-induced airway inflammation and damage via regulating airway epithelial cell apoptosis in a manner dependent on HMGB1-mediated signaling inhibition

Abstract

Background House dust mite (HDM) inhalation can cause airway epithelial damage which is implicated in the process of airway inflammation in asthma. High mobility group box 1 (HMGB1) is critically required for cellular damage and apoptosis as an important endogenous danger signal. Recently, Clara cell 16KDa protein (CC16) has been identified to exert anti-inflammatory and immunomodulatory influence in various injury-related diseases model. However, little is known about its ability to protect against airway epithelial injury in allergic asthma. This study was aimed to clarify the protective roles of CC16 on airway epithelia in HDM-induced asthma and the regulation of HMGB1 by CC16. Methods Mice were sensitized and challenged by HDM extract and administrated intranasally with CC16 (5 μg/g or 10 μg/g) or saline in the challenged period. The BEAS-2B human airway epithelial cell line were cultured with CC16 or the control vehicle and then exposed to HDM. Knockdown or overexpression of HMGB1 was induced by cell transfection or intratracheal injection of recombinant adenovirus. Results CC16 treatment decreased airway inflammation and histological damage of airway epithelium dose-dependently in HDM-induced asthma model. Airway epithelia apoptosis upon HDM stimulation was noticeably abrogated by CC16 in vivo and in vitro. In addition, upregulation of HMGB1 expression and its related signaling were also detected under HDM conditions, while silencing HMGB1 significantly inhibited the apoptosis of BEAS-2B cells. Furthermore, the activity of HMGB1-mediated signaling was restrained after CC16 treatment whereas HMGB1 overexpression abolished the protective effect of CC16 on HDM-induced airway epithelia apoptosis. Conclusions Our data confirm that CC16 attenuates HDM-mediated airway inflammation and damage via suppressing airway epithelial cell apoptosis in a HMGB1-dependent manner, suggesting the role of CC16 as a potential protective option for HDM-induced asthma.

Allergen-specific immunotherapy with Alutard SQ improves allergic inflammation in house-dust mites-induced allergic asthma rats through inactivation of the HMGB1/TLR4/NF-κB pathway

“…A study recently reported HMGB1 upregulation in HDM-induced asthmatic rats, HMGB1 overexpression aggravated HDM-induced inflammatory responses and airway damage ( 12 ). Herein, we investigated whether Alutard SQ could regulate HMGB1 expression in HDM-challenged asthma.…”

“…The interaction of HDM inhalation and airway epithelial cells directly caused airway epithelium dysfunction. HDM stimulates airway epithelial cells to release epithelial-derived cytokines, and recruit neighboring innate and adaptive immune cells including DCs, T-cells (such as Th2, Th1, and Th17), B-cells, eosinophils, and neutrophils, which are essential for asthma pathogenesis ( 12 , 30 , 31 ). Amongst these cytokines, IL-13, IL-33, TSLP, CCL5, CCL7, CCL17, CCL22, IFN-γ, IL-4, and several eotaxins strongly direct or support the development of a Th2 polarized inflammation ( 30 , 32 ).…”

CC16-TNF-α negative feedback loop formed between Clara cells and normal airway epithelial cells protects against diesel exhaust particles exposure-induced inflammation

“…We were curious about whether there are links between DEP-inhibited CC16 secretion in epithelial Clara cells and DEP-induced the inflammatory response in BEAS-2B airway epithelial cells without CC16 expression? Increasing evidence showed that CC16 protects airway epithelial cells from environmental stimuli, such as house dust mite and cigarette smoke exposure [20][21][22]. Herein, the role of CC16 in bronchial epithelial cells exposed to DEP was investigated.…”

“…It is well known that CC16 has anti-inflammatory and antioxidant effects [14][15][16][17][18][19]. The change in CC16 level not only has a profound effect on the composition of the airway surface fluid, but also affects the response of the airway epithelium to environmental stimuli [20][21][22]. For instance, CC16 mitigates house dust miteinduced airway inflammation and damage via regulation of airway epithelial cell apoptosis [20]; and CC16 level is also correlated with cigarette smoke exposure in bronchial epithelial cells, and protects against lung injury in smokers [21].…”

Cc16 Role in Bronchiolitis in Young Children

“…Measuring the CC16 concentration makes it possible to assess a degree of Club cell damage, and, therefore, the magnitude of respiratory epithelium damage and bronchial dysfunction [9]. Given the above, growing attention has been paid in the scientific literature to the research of new laboratory markers for diagnostics of bronchiolitis in young children.…”