Loss of CD73 prevents accumulation of alternatively activated macrophages and the formation of prefibrotic macrophage clusters in irradiated lungs.
While radiotherapy is a mainstay for cancer therapy, pneumonitis and fibrosis constitute dose-limiting side effects of thorax and whole body irradiation. So far, the contribution of immune cells to disease progression is largely unknown. Here we studied the role of ecto-5'-nucelotidase (CD73)/adenosine-induced changes in the myeloid compartment in radiation-induced lung fibrosis. C57BL/6 wild-type or CD73-/-mice received a single dose of whole thorax irradiation (WTI, 15 Gy). Myeloid cells were characterized in flow cytometric, histologic, and immunohistochemical analyses as well as RNA analyses. WTI induced a pronounced reduction of alveolar macrophages in both strains that recovered within 6 wk. Fibrosis development in wild-type mice was associated with a time-dependent deposition of hyaluronic acid (HA) and increased expression of markers for alternative activation on alveolar macrophages. These include the antiinflammatory macrophage mannose receptor and arginase-1. Further, macrophages accumulated in organized clusters and expressed profibrotic mediators at ≥25 wk after irradiation (fibrotic phase). Irradiated CD73-/-mice showed an altered regulation of components of the HA system and no clusters of alternatively activated macrophages. We speculate that accumulation of alternatively activated macrophages in organized clusters represents the origins of fibrotic foci after WTI and is promoted by a cross-talk between HA, CD73/adenosine signaling, and other profibrotic mediators.-De Leve, S., Wirsdörfer, F., Cappuccini, F., Schütze, A., Meyer, A. V., Röck, K., Thompson, L. F., Fischer, J. W., Stuschke, M., Jendrossek, V. Loss of CD73 prevents accumulation of alternatively activated macrophages and the formation of prefibrotic macrophage clusters in irradiated lungs.
Institute of Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany.
Simone
S
de Leve
Institute of Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany.
Florian
F
Wirsdörfer
Institute of Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany.
Federica
F
Cappuccini
Pharmacology and Clinical Pharmacology, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
Alexandra
A
Schütze
Institute of Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany.
Alina V
AV
Meyer
Pharmacology and Clinical Pharmacology, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
Katharina
K
Röck
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Linda F
LF
Thompson
Pharmacology and Clinical Pharmacology, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
Jens W
JW
Fischer
Department of Radiation Oncology, University Hospital Essen, Essen, Germany.
Martin
M
Stuschke
Institute of Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany; verena.jendrossek@uni-due.de.
Verena
V
Jendrossek
D015720:5'-Nucleotidase / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002448:Cell Adhesion; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006820:Hyaluronic Acid / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000528:radiation effects*; D016676:Macrophages, Alveolar / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000209:etiology; D015398:Signal Transduction
D039481:CD11b Antigen; D006820:Hyaluronic Acid; D015720:5'-Nucleotidase; D000241:Adenosine
adenosine; hyaluronan; pneumonitis; pulmonary fibrosis; thorax irradiation