Low doses of radiation increase the immunosuppressive profile of lung macrophages during viral infection and pneumonia

Abstract

Patients with severe COVID-19 have a marked inflammatory state characterized by a cytokine storm syndrome. Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in 14% of the reported cases. Several therapeutic approaches are under investigation but safety and potential efficacy remain to be determined. Chest irradiation at equivalent doses below 1 Gy has been used successfully in the past to treat pneumonia.However, after the onset of effective antimicrobial agents, the use of low doses in the treatment of patients has been discontinued and the involved mechanism remained unknown.The objective of this study was to determine the mechanism by which low doses of radiation therapy (RT) protect the lung from inflammation. Nerve-and airway-associated macrophages (NAMs) and the pro-versus anti-inflammatory cytokine balance (IL6-IFNγ/IL-10) were recently shown to regulate lung inflammation. Here, we used Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid [Poly(I:C)] and lipopolysaccharide (LPS) in human lung macrophages and murine model of lung inflammation for functional assays. Our results show that irradiation of Poly(I:C)-stimulated human lung macrophages in vitro using low doses of RT (0.5-1 Gy) increased IL-10 secretion and decreased IFNγ production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased in vitro with low doses of RT. Furthermore, using experimental models (LPS-and Poly(I :C)-induced lung inflammation), we showed that chest irradiation using low doses of RT significantly increased the percentage of NAMs producing IL-10, leading to lung protection from inflammation. Altogether, our data highlight one of the mechanisms by which low doses of RT regulate lung inflammation and positively favor anti-inflammatory cytokine secretion by lung macrophages. These data strongly suggest that low doses of RT could be used in order to mitigate lung inflammatory processes in situations such as COVID-19induced ARDS.

Low-dose lung radiotherapy for COVID-19 lung disease: a preclinical efficacy study in a bleomycin model of pneumonitis

“…Of these, only 1.0 Gy demonstrated signs of efficacy, although we recognise that the other doses underwent less comprehensive evaluation. This observation is largely consistent with the data generated by Meziani and colleagues in lipopolysaccharide (LPS) and H1N1 influenza models of lung injury, although responses to 0.5 Gy were also observed in some of the histological and cytological readouts reported in this study (11).…”

“…Recent preclinical studies have generated preliminary data to indicate that LDLR (0.5-1 Gy) reduces pneumonitis in lipopolysaccharide (LPS) and influenza virus mouse models (11). These diverse but limited bodies of evidence have underpinned early phase clinical trials of LDLR for acutely unwell COVID-19 patients in several countries including the USA, India and Spain.…”

In Reply to Bevelacqua et al

“…In addition, our patients did not receive the prescribed dose of 1 Gy to the whole lungs. Rather, as described in the manuscript, the lungs received antiinflammatory doses in the range of 0.5 -1.0 Gy, which appears adequate based on recent preclinical research [2,3].…”

Immunomodulation Through Low-Dose Radiation for Severe COVID-19: Lessons From the Past and New Developments

“…The M1-to M2-phenotypic conversion may be important to clinical outcomes of inflammatory disease, as the M2-type macrophages secrete the anti-inflammatory cytokines, interleukin (IL)-10 and TGF-b1 and suppress the proinflammatory cytokine IL-6. 33,34 Patients with critical COVID-19 illness (i.e.-hyperinflammation) have been shown to have high levels of cytokines, particularly IL-6 22 as constituent to cytokine storm. Downregulating proinflammatory cytokines in COVID-19 hyperinflammation could prevent the onset of a critical stage of disease.…”