The human cathelicidin LL37 and mitochondrial DAMPs induce airway inflammation in epithelial cells and mice

Abstract

Cigarette smoke (CS) exposure is known to induce immunogenic cell death and release of Damage Associated Molecular Patterns (DAMPs) from airway epithelial cells. Previously, we have shown that CS exposure induces release of a specific pattern of DAMPs into BAL fluid of mice and serum of COPD patients. However, the role of DAMPs in CS-induced airway inflammation is still unknown. Here, we hypothesized that DAMPs increase pro-inflammatory activity of airway epithelial cells and induce airway inflammation. Airway epithelial cells isolated from COPD patients and healthy controls were stimulated with several DAMPs, including LL37 and mitochondrial DAMPs (MTDs). The levels of CXCL8 in supernatant were used as a marker for pro-inflammatory activity. Furthermore, mice previously determined as susceptible (BALB/cByJ) or non-susceptible (DBA/2J) for the development of CS-induced neutrophilic airway inflammation, were treated intranasally with recombinant LL37, isolated MTDs or BSA as a control, and inflammatory cell count and KC levels in BAL were analyzed. Both LL37 and MTDs were able to significantly induce CXCL8 secretion in epithelial cells from both COPD patients and healthy controls. Upon treatment with LL37 and MTDs, neutrophilic airway inflammation was induced in susceptible BALB/cByJ mice but not in non-susceptible DBA/2J mice. In conclusion, we show for the first time that LL37 and MTDs are potent inducers of pro-inflammatory responses, directly activating bronchial epithelial cells and inducing neutrophilic inflammation in mice. Thus, induction of immunogenic cell death by CS and subsequent release of LL37 and MTDs may contribute to airway inflammation in COPD.