Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment

• DOI: 10.1016/j.xcrm.2022.100833
• Publication Date: 2022-11-16T05:02:42Z
• Authors: Cedric Bosteels; Karel F.A. Van Damme; Elisabeth De Leeuw; Jozefien Declercq; Bastiaan Maes; Victor Bosteels; Levi Hoste; Leslie Naesens; Nincy Debeuf; Julie Deckers; Basiel Cole; Marion Pardons; Daniela Weiskopf; Alessandro Sette; Yannick Vande Wey...; Thomas Malfait; Stefaan J. Vandec...; Ingel K. Demedts; Hans Slabbynck; Sabine Allard; Pieter Depuydt; Eva Van Braeckel; Jozefien De Clercq; Liesbet Martens; Sam Dupont; Ruth Seurinck; Niels Vandamme; Filomeen Haerynck; Debasish F. Roych...; Linos Vandekerckhove; Martin Guilliams; Simon J. Tavernier; Bart N. Lambrecht
• Keywords: EXPRESSION; PNEUMONIA; DEVELOP; 0301 basic medicine; SARPAC; virus; Research & Experimental Medicine; Article; 03 medical and health sciences; Macrophages, Alveolar; Medicine and Health Sciences; Humans; CELL; Lung; Science & Technology; FETAL MONOCYTES; Macrophages; leukine; Granulocyte-Macrophage Colony-Stimulating Factor; COVID-19; GM-CSF; EPITHELIAL-CELLS; Cell Biology; COLONY-STIMULATING FACTOR; 3. Good health; DENDRITIC; CITE-seq; DIFFERENTIATION; Medicine, Research & Experimental; TRIAL; alveolar macrophage; sargramostim; Life Sciences & Biomedicine; DENDRITIC CELL; RCT; LUNG

GM-CSF promotes myelopoiesis and inflammation, blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar is, however, required monocytes to differentiate into alveolar macrophages (AMs) that control homeostasis. By mapping cross-species AM development clinical lung samples, we discovered COVID-19 marked by defective GM-CSF-dependent instruction accumulation of pro-inflammatory macrophages. In multi-center, open-label RCT in 81 non-ventilated patients with respiratory failure, found inhalation rhu-GM-CSF did not improve mean oxygenation parameters compared standard treatment. However, more on had response, induced higher numbers virus-specific CD8 effector lymphocytes class-switched B cells, without exacerbating systemic This translational proof-of-concept study provides rationale further testing inhaled non-invasive gas exchange simultaneously boost antiviral immunity COVID-19. registered at ClinicalTrials.gov (NCT04326920) EudraCT (2020-001254-22).