Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS
Authors: Frederic Mourcin
Mathieu Lesouhaitier
Arnaud Gacouin
Marion Guirriec
Jaroslaw W Zmijewski
Laure-Line Berthelot
Arnaud Chalin
Erwan Dumontet
Fabrice Uhel
Yves Le Tulzo
Murielle Grégoire
Mallorie Kerjouan
Michel Samson
Adrien Tissot
Karin Tarte
Stéphane Jouneau
Jean-Marc Tadié
Journal: European Respiratory Journal (2018)
Discipline: CLINICAL MEDICINE
Keywords: Neutrophil extracellular traps (NETs); acute respiratory distress syndrome (ARDS); AMP-activated protein kinase (AMPK); high-mobility group box 1 (HMGB1); efferocytosis
Affiliations: CHU Rennes, Pôle Biologie, Rennes, France., Université Rennes 1, INSERM, EFS Bretagne, UMR U1236, Rennes, France., CHU Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France., Inserm CIC-1414, Faculté de Médecine, Université Rennes 1, Rennes, France., Université Rennes 1, INSERM, UMR U1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France., Université de Nantes, INSERM, UMR_S 1064, Centre de Recherche en Transplantation et Immunologie (CRTI), Nantes, France., CHU Nantes, Service de Pneumologie, Nantes, France., CHU Rennes, Service de Pneumologie, Rennes, France., Dept of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

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. 

Retracted: No

PubPeer comments:
 ![file] The figure 5f is a western blot band collection of ARDS and control group. , 
 #1 As specified in the figure legend, the figure 5f is a Western blot representative image. We believed that the withdrawal of some bands corresponding to other conditions did not alter the interpretation of the results. This was not an assembly of two different membranes. ![file] Full length blots are presented in the images below. ![file] Uncropped Western blot raw data (related to figure 5F) ![file] ![file] ![file] ,