Abstract
A single-nucleotide polymorphism of neutrophil cytosolic factor 1 (Ncf1), leading to an impaired generation of reactive oxygen species (ROS), is a causative genetic factor for autoimmune disease. To study a possible tumor protection effect by the Ncf1 mutation in a manner dependent on cell types, we used experimental mouse models of lung colonization assay by B16F10 melanoma cells. We observed fewer tumor foci in Ncf1 mutant mice, irrespective of αβT, γδT, B-cell deficiencies, or of a functional Ncf1 expression in CD68-positive monocytes/macrophages. The susceptibility to tumor colonization was restored by the human S100A8 (MRP8) promoter directing a functional Ncf1 expression to granulocytes. This effect was associated with an increase of both ROS and interleukin 1 beta (IL-1β) production from lung neutrophils. Moreover, neutrophil depletion by anti-Ly6G antibodies increased tumor colonization in wild type but failed in the Ncf1 mutant mice. In conclusion, tumor colonization is counteracted by ROS-activated and IL-1β-secreting tissue neutrophils.
Highlights
A single-nucleotide polymorphism of neutrophil cytosolic factor 1 (Ncf1), leading to an impaired generation of reactive oxygen species (ROS), is a causative genetic factor for autoimmune disease
To further study the cell-type-specific effect of ROS deficiency, we investigated the role of macrophages and monocytes
We used the transgenic MN mice (Ncf1*/*.MN+/+) expressing NCF1 restricted to CD68-positive cells, and a fluorophore dihydrorhodamine 123 (DHR) to measure the ROS production of individual cells upon stimulation with phorbol 12-myristate 13-acetate (PMA)
Summary
A single-nucleotide polymorphism of neutrophil cytosolic factor 1 (Ncf1), leading to an impaired generation of reactive oxygen species (ROS), is a causative genetic factor for autoimmune disease. To study a possible tumor protection effect by the Ncf[1] mutation in a manner dependent on cell types, we used experimental mouse models of lung colonization assay by B16F10 melanoma cells. The susceptibility to tumor colonization was restored by the human S100A8 (MRP8) promoter directing a functional Ncf[1] expression to granulocytes. This effect was associated with an increase of both ROS and interleukin 1 beta (IL-1β) production from lung neutrophils. This study provides insights into the role of NOX2-derived ROS in driving tumor colonization through a neutrophil and IL-1β-dependent pathway
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