Publication Date
10-20-2023
Journal
iScience
DOI
10.1016/j.isci.2023.107813
PMID
37810211
PMCID
PMC10551843
PubMedCentral® Posted Date
9-1-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Clinical genetics, Molecular medicine, Immune response
Abstract
Altered myeloid inflammation and lymphopenia are hallmarks of severe infections. We identified the upregulated EN-RAGE gene program in airway and blood myeloid cells from patients with acute lung injury from SARS-CoV-2 or other causes across 7 cohorts. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGEhi myeloid cells express features consistent with suppressor cell functionality, including low HLA-DR and high PD-L1. Sustained EN-RAGE program expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell dysfunction markers. IL-6 upregulated many EN-RAGE program genes in monocytes in vitro. IL-6 signaling blockade by tocilizumab in a placebo-controlled clinical trial led to rapid normalization of EN-RAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.
Graphical Abstract
Included in
Clinical Epidemiology Commons, COVID-19 Commons, Critical Care Commons, Internal Medicine Commons, Medical Sciences Commons, Pulmonology Commons, Sleep Medicine Commons