Proteolytic cleavage of HLA class II by human neutrophil elastase in pneumococcal pneumonia

Bacterial and viral respiratory infections can initiate acute lung injury and acute respiratory distress syndrome. Neutrophils and their granule enzymes, including neutrophil elastase, are key mediators of the pathophysiology of acute respiratory failure. Although intracellular neutrophil elastase functions as a host defensive factor against pathogens, its leakage into airway spaces induces degradation of host connective tissue components. This leakage disrupts host innate immune responses via proteolytic cleavage of Toll-like receptors and cytokines. Here, we investigated whether neutrophils possess proteases that cleave adaptive immune molecules. We found that expression of the human leukocyte antigen (HLA) class II molecule HLA-DP beta 1 was decreased in THP-1-derived macrophages treated with supernatants from dead neutrophils. This decreased HLA-DP beta 1 expression was counteracted by treatment with neutrophil elastase inhibitor, suggesting proteolytic cleavage of HLA-DP beta 1 by neutrophil elastase. SDS-PAGE showed that neutrophil elastase cleaved recombinant HLA-DP alpha 1, -DP beta 1, -DQ alpha 1, -DQ beta 1, -DR alpha, and -DR beta 1. Neutrophil elastase also cleaved HLA-DP beta 1 on extracellular vesicles isolated from macrophages without triggering morphological changes. Thus, leakage of neutrophil elastase may disrupt innate immune responses, antigen presentation, and T cell activation. Additionally, inhibition of neutrophil elastase is a potential therapeutic option for treating bacterial and viral pneumonia.

Automated summary

Bacterial and viral respiratory infections can cause acute lung injury and acute respiratory distress syndrome, with neutrophils and their granule enzymes playing a key role in the pathophysiology. Neutrophil elastase leakage into airway spaces may disrupt innate immune responses by cleaving Toll-like receptors and cytokines. Inhibition of neutrophil elastase could be a potential therapeutic option for bacterial and viral pneumonia.