Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS

Abstract

Exaggerated release of neutrophil extracellular traps (NETs) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMP-activated protein kinase (AMPK) and high-mobility group box 1 (HMGB1), which may contribute to effectiveness of efferocytosis, thereby reducing inflammation and ARDS severity.We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluid from control and ARDS patients could affect NET formation and efferocytosis. Metformin (an AMPK activator) and neutralising antibody against HMGB1 were applied to improve efferocytosis and NET clearance.Neutrophils from ARDS patients showed significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS patients. Exposure of neutrophils to ARDS BAL fluid promoted NET production, while control BAL fluid had no effect. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralisation of HMGB1 in BAL fluid improved efferocytosis and NET clearance.In conclusion, restoration of AMPK activity with metformin or specific neutralisation of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS.

Death to the neutrophil! A resolution for acute respiratory distress syndrome?

“…It is the latter subject that was tackled in the study published in the current issue of the European Respiratory Journal by GRÉGOIRE et al [9]. They investigated the role and clearance of neutrophils and NETs in human ARDS and offer new insights into these processes.…”

“…Thus, it is intriguing that this signalling pathway is defective during ARDS. Moreover, metformin is a widely used, clinically approved drug and these results from GRÉGOIRE et al [9] therefore provide a compelling rationale for further investigation into its use in ARDS.…”

“…Animal models cannot fully recapitulate the human condition; thus, bench-to-bedside and bedside-back-to-bench approaches will be important for developing effective treatment strategies for ARDS. The current study by GRÉGOIRE et al [9] provides some intriguing new insights into human ARDS, including a potential therapeutic target that could help in the resolution of inflammation. ARDS is a complex syndrome and further research into the mechanisms involved and new therapeutics is needed to improve its prevention and treatment.…”

“…GRÉGOIRE et al [9] found that circulating neutrophils isolated from the ARDS patients produced significantly more NETs when stimulated with phorbol myristate acetate (PMA) compared to neutrophils obtained from healthy donors. While PMA causes lytic neutrophil NET release (referred to as NETosis) and has limited biological relevance, much more interesting was the finding that when neutrophils were exposed to BAL fluid obtained from either control or ARDS patients, only the ARDS BAL fluid stimulated NET release.…”

“…In a final set of experiments, GRÉGOIRE et al [9] evaluated possible therapeutic targets to increase NET clearance and efferocytosis by the ARDS patients' monocyte-derived macrophages. They found that neutralising HMGB1 increased the clearance of apoptotic neutrophils, yet had no effect on NET uptake.…”