SRA

Macrophages not only derive from circulating blood monocytes, but also originate from embryonic progenitors that can proliferate. This dichotomic origin has an impact on macrophage functions in steady state and pathological conditions. Long needle-like carbon nanotubes (CNT) damage serous membranes and induce mesothelioma like asbestos fibers. Macrophages predominantly infiltrate CNT-induced injured tissue and contribute to cancer development. Here, we revealed the exact ontogeny of macrophage populations after CNT exposure by comparing the response to needle-like mesotheliomagenic CNT-7 with tangled-like non-mesotheliomagenic CNT-T. In a rat peritoneal cavity model, both CNT induced a rapid and complete depletion of MHCIIlow resident macrophages generating an empty niche available for macrophage repopulation. Macrophage disappearance after mesotheliomagenic CNT-7 was followed by a substantial inflammatory reaction, and macrophage replenishment completed after 7 days. Fifteen days after non-mesotheliomagenic CNT-T, macrophage repopulation was incomplete and accompanied by a limited inflammatory reaction. Cell depletion experiments, flow cytometry and RNA-seq analysis demonstrated that, after CNT-7, resident macrophages were mainly replaced by an influx of monocytes, which differentiated locally into MHCIIhigh inflammatory macrophages. In contrast, the low inflammatory response induced by CNT-T was linked to the activation of self-renewing MHCIIlow macrophages. In conclusion, the mesotheliomagenic response to CNT specifically relies on macrophage niche recolonization by monocytic progenitors. The homeostasis returns after exposure to non mesotheliomagenic CNT-T involves, in contrast, a macrophage maintenance by proliferation. Macrophage depletion and repopulation are thus decisive events characterizing the carcinogenic activity of fibrous particles. Overall design: RNA-sequencing analysis of peritoneal macrophages purified from mesotheliomagenic (CNT-7) and non mesotheliomagenic (CNT-T) carbon nanotube treated rats. There are 4 rats for each treatment.