Low doses of radiation therapy increase the immunosuppressive profile of lung macrophages via IL-10 production and IFNγ/IL-6 suppression: a therapeutic strategy to counteract lung inflammation?

Abstract

Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe COVID-19. Recently, early clinical data reported the efficacy of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown. Here, we used airways-instilled lipopolysaccharide (LPS) and influenza virus (H1N1) as murine models of pneumonia, and Tolllike receptor (TLR)-3 stimulation in human lung macrophages. Low doses RT (0.5-1 Gy) decreased LPS induced pneumonia, and increased the percentage of Nerve- and Airway-associated Macrophages (NAMs) producing IL-10. During H1N1 viral infection, we observed decreased lung tissue damage and immune cell infiltration in irradiated animals. Low doses RT increased IL-10 production by infiltrating immune cells into the lung. Irradiation of TLR-3 ligand-stimulated human lung macrophages ex vivo increased IL-10 secretion and decreased IFN{gamma} production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased. Our data highlight one of the mechanisms by which low doses RT regulate lung inflammation and skew lung macrophages towards an anti-inflammatory profile. These data provide the preclinical rationale for the use and for the optimization of low doses RT in situations such as COVID-19-induced ARDS.