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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?

View ORCID ProfileLydia Meziani, Charlotte Robert, Pierre Mordant, Eric Deutsch
doi: https://doi.org/10.1101/2020.05.11.077651
Lydia Meziani
1INSERM U1030, Radiothérapie Moléculaire et Innovations Thérapetuiques, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
2Labex LERMIT, DHU TORINO, SIRIC SOCRATE
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Charlotte Robert
1INSERM U1030, Radiothérapie Moléculaire et Innovations Thérapetuiques, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
2Labex LERMIT, DHU TORINO, SIRIC SOCRATE
3Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France
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Pierre Mordant
4Department of vascular surgery, thoracic surgery, and lung transplantation, Bichat Hospital, Assistance Publique – Hôpitaux de Paris, INSERM U1152, Université de Paris, Paris, France
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Eric Deutsch
1INSERM U1030, Radiothérapie Moléculaire et Innovations Thérapetuiques, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
2Labex LERMIT, DHU TORINO, SIRIC SOCRATE
3Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France
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  • For correspondence: eric.deutsch@gustaveroussy.fr lydia.meziani@gustaveroussy.fr
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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-19-induced ARDS.

Competing Interest Statement

Declarations: Competing interests: The authors declare that they have no potential conflicts of interest related to this work. E. DEUTSCH reports grants and personal fees from ROCHE GENENTECH, grants from SERVIER, grants from ASTRAZENECA, grants and personal fees from MERCK SERONO, grants from BMS, grants from MSD, outside the submitted work Acknowledgements: The authors thank Patrick Gonin, Karine Ser-Le Roux (PFEP platform), Valérie Rouffiac, Philippe Rameau and Cyril Catelain (PFIC platform) at Gustave Roussy for technical assistance.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 13, 2020.
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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?
Lydia Meziani, Charlotte Robert, Pierre Mordant, Eric Deutsch
bioRxiv 2020.05.11.077651; doi: https://doi.org/10.1101/2020.05.11.077651
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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?
Lydia Meziani, Charlotte Robert, Pierre Mordant, Eric Deutsch
bioRxiv 2020.05.11.077651; doi: https://doi.org/10.1101/2020.05.11.077651

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