Axis 3 "Myeloid cell reprogramming and acute inflammation"

• Jean-Marc Tadié, MD PhD, HDR (PI)
• Murielle Grégoire (engineer)
• Mathieu Lesouhaitier, MD (PhD student)
• Florian Reizine MD (PhD student)

Severe impairment of innate and adaptive immune functions has been described in critically ill state and has been associated with nosocomial infection (NI) acquisition and worst outcome. Identical immune dysfunctions on both monocyte and lymphocyte have been observed after cardiac surgery with cardiopulmonary bypass (CPB) or acute respiratory distress syndrome (ARDS), directly or indirectly impairing the function of almost all innate and adaptive immune cell subsets.
Our aim is to understand underlying mechanism involved in acquired immune dysfunction.

Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS

European Respiratory Journal 2018

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 neutralizing 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 neutralization of HMGB1 in BAL fluid improved efferocytosis and NET clearance. In conclusion, restoration of AMPK activity with metformin or specific neutralization of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS.

Venoarterial extracorporeal membrane oxygenation induces early immune alterations

Critical Care 2021

We studied immune alterations induced by VA-ECMO initiation using cytometry analysis to characterize immune cell changes and enzyme-linked immunosorbent assay (ELISA) to explore plasma cytokine levels. To analyze specific changes induced by VA-ECMO initiation, nine patients under VA-ECMO (VA-ECMO patients) were compared to nine patients with cardiogenic shock (control patients).
Baseline immune parameters were similar between the two groups. VA-ECMO was associated with a significant increase in circulating immature neutrophils with a significant decrease in C5a receptor expression. Furthermore, we found that VA-ECMO initiation was followed by lymphocyte dysfunction along with myeloid-derived suppressor cells (MDSC) expansion. ELISA analysis revealed that VA-ECMO initiation was followed by an increase in pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α along with IL-10, a highly immunosuppressive cytokine.

SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage

A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission.
We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation.

•    Maintaining Mechanical Ventilation During Cardiopulmonary Bypass for Cardiac Surgery (VECAR). NCT03372174
•    Immuno Nutrition by L-citrulline for Critically Ill Patients (Immunocitre). NCT02864017
•    ICITRU : Randomized Trial of Immunonutrition With L-citrulline in Patients Hospitalized in Intensive Care for Sepsis or Septic Shock (ICITRU). NCT04513288
•    Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome (CACOLAC). NCT04404426