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

Abstract

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 β1 was decreased in THP-1-derived macrophages treated with supernatants from dead neutrophils. This decreased HLA-DP β1 expression was counteracted by treatment with neutrophil elastase inhibitor, suggesting proteolytic cleavage of HLA-DP β1 by neutrophil elastase. SDS-PAGE showed that neutrophil elastase cleaved recombinant HLA-DP α1, -DP β1, -DQ α1, -DQ β1, -DR α, and -DR β1. Neutrophil elastase also cleaved HLA-DP β1 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.

Innate immune deficiencies are associated with severity and poor prognosis in patients with COVID-19

“…CD10 is a maturity marker, and low CD10 expression has been associated with immature and less functional neutrophils 38,39 . Finally, neutrophil elastase enzymatic activity is strongly suspected to participate in lung injury during ARDS 40 , and is also able to impair adaptive immune responses and facilitate viral entry 41,42 . Thus, compared with non-ICU patients, ICU patients present additional features of proinflammatory immune components but also immature and immunosuppressive cells that contribute to global immune dysfunction and may explain their more severe condition.…”

Severe COVID-19 is characterized by the co-occurrence of moderate cytokine inflammation and severe monocyte dysregulation

“…In particular, the secretion of neutrophilic elastase is associated with the severe forms of the disease [ 47 , 48 ]. However, once released this elastase has the property of lysing nearby HLA-DR molecules [49] . In our series, we observed an increase in this marker in our most severe patients and an inverse correlation with the expression of HLA-DR (data not shown).…”

Clarithromycin Inhibits Pneumolysin Production via Downregulation of ply Gene Transcription despite Autolysis Activation

“…Subsequently, the arterial oxygen saturation was measured using MouseOx Plus (STARR Life Sciences Corp., Oakmont, PA, USA) according to manufacturer’s instructions, and the mice were sacrificed immediately. To obtain BALF, 1 ml PBS was introduced into mouse lungs and slowly aspirated ( 56 ). BALF samples were plated onto 5% sheep blood agar plates and cultured aerobically to enumerate the recovered CFU.…”