Epithelial cell-specific role of HMGB1 in murine lungs with muco-obstructive lung disease

Abstract

Abstract Introduction Mucoobstructive lung diseases are characterized by defective mucociliary clearance, mucin hypersecretion, and mucoobstruction. High mobility group box 1 protein (HMGB1) plays a key role as an inflammatory mediator. However, the role of HMGB1 in mucoobstructive lung diseases remains unclear. Using Scnn1b-Tg+ mice, a mouse model of cystic fibrosis, we hypothesized that the airway epithelial cell-specific HMGB1 acts as an anti-inflammatory mediator in the Scnn1b-Tg+ lungs. Methods Airway epithelial cell-specific HMGB1-deficient (CCSP-iCre+/Hmgb1flox/flox) and control (CCSP-iCre− /Hmgb1flox/flox) mice were generated. The bronchoalveolar lavage fluid (BALF) and lung tissue were collected for endpoints analyses. Results Compared with wild-type (WT) mice, HMGB1 expression was significantly increased in BALF and airway epithelial cells of Scnn1b-Tg+ mice. Unlike HMGB1-sufficient Scnn1b-Tg+ mice, HMGB1-deficient Scnn1b-Tg+ mice exhibited enhanced lung inflammation evident from the elevated total protein and dsDNA contents in the BALF. HMGB1 deletion in airway epithelial cells in Scnn1b-Tg+ mice also exaggerated immune cell recruitment, which was accompanied by increased levels of chemokines and cytokines, including KC, G-CSF, MCP-1, MIP-2, MIP-1α, MIP-1β, and IP-10. Furthermore, HMGB1 deletion in airway epithelial cells in Scnn1b-Tg+ mice enhanced the type 2 inflammation manifested by increased levels of Th2 cytokines such as IL-4 and IL-5. Additionally, HMGB1-deficient Scnn1b-Tg+ mice showed increased airway mucus plugging and impaired bacterial clearance. Conclusion Epithelial cell-derived HMGB1 may play an anti-inflammatory role in murine lungs with mucoobstructive lung disease. Supported by NIEHS (RO1, ES030125)