Monocytic Ontogeny of Regenerated Macrophages Characterizes the Mesotheliomagenic Responses to Carbon Nanotubes

Our plain-English summary of Monocytic Ontogeny of Regenerated Macrophages Characterizes the Mesotheliomagenic Responses to Carbon Nanotubes, by M. Orsi, M. Palmai-Pallag, Y. Yakoub, et al (Frontiers in Immunology, 2021).

The study

• Authors: M. Orsi, M. Palmai-Pallag, Y. Yakoub, S. Ibouraadaten, M. De Beukelaer, C. Bouzin, B. Bearzatto, J. Ambroise, J.L. Gala, D. Brusa, D. Lison, F. Huaux
• Journal: Frontiers in Immunology
• Published: 2021;12:666107
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Macrophages are not only derived from circulating blood monocytes or embryonic precursors but also expand by proliferation. The origin determines macrophage fate and functions in steady state and pathological conditions. Macrophages predominantly infiltrate fibre-induced mesothelioma tumors and contribute to cancer development. Here, we revealed their ontogeny by comparing the response to needle-like mesotheliomagenic carbon nanotubes (CNT-7) with tangled-like non-mesotheliomagenic CNT-T. In a rat peritoneal cavity model of mesothelioma, both CNT induced a rapid macrophage disappearance reaction (MDR) of MHCIIlow resident macrophages generating an empty niche available for macrophage repopulation. Macrophage depletion after mesotheliomagenic CNT-7 was followed by a substantial inflammatory reaction, and macrophage replenishment completed after 7 days. Thirty days after non-mesotheliomagenic CNT-T, macrophage repopulation was still incomplete and accompanied by a limited inflammatory reaction. Cell depletion experiments, flow cytometry and RNA-seq analysis demonstrated that, after mesotheliomagenic CNT-7 exposure, 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 associated by the accumulation of self-renewing MHCIIlow macrophages that initially derive from monocytes. In conclusion, the mesotheliomagenic response to CNT specifically relies on macrophage niche recolonization by monocyte-derived inflammatory macrophages. In contrast, the apparent homeostasis after non-mesotheliomagenic CNT treatment involves a macrophage regeneration by proliferation. Macrophage depletion and repopulation are thus decisive events characterizing the carcinogenic activity of particles and fibres.

Copyright © 2021 Orsi, Palmai-Pallag, Yakoub, Ibouraadaten, De Beukelaer, Bouzin, Bearzatto, Ambroise, Gala, Brusa, Lison and Huaux.

In plain English

This was an animal experiment in a rat peritoneal model used to study mesothelioma-related responses to carbon nanotubes. Female Wistar rats, in groups of 4 to 5, received a single intraperitoneal injection of 2 mg of needle-like mesotheliomagenic CNT-7 (Mitsui MWCNT-XNRI-7) or tangled non-mesotheliomagenic CNT-T, and were killed after 3 hours or 1, 3, 7, 15 or 30 days. Both nanotubes caused resident macrophages to disappear from the peritoneal fluid from 3 hours to 3 days. After CNT-7, macrophage regeneration was almost complete by 7 days and was accompanied by neutrophil influx and release of IL-1b, IL-6, IL-17A and GRO/KC, with CCL2 and M-CSF raised at 3 hours; after CNT-T, repopulation was slower and still incomplete at 30 days. Both materials were cytotoxic to macrophages in vitro. RNA-seq showed enrichment of an MHCIIhigh SPM signature after CNT-7 and of MHCIIlow LPM and cell-cycle genes after CNT-T; busulfan depletion abolished replenishment after CNT-7. The authors concluded that macrophage regeneration after CNT-7 depends on monocytes.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (rat intraperitoneal model) with in vitro cytotoxicity testing, flow cytometry, RNA-seq and cell-depletion experiments
• Who was studied: Specific pathogen free female Wistar rats, 8 weeks old, 200 g, in groups of 4 to 5 per treatment, studied at UCLouvain, Brussels, Belgium; killed 3 hours and 1, 3, 7, 15 or 30 days after injection
• Exposure: Single intraperitoneal injection of 2 mg of needle-like multi-walled carbon nanotubes CNT-7 (MWCNT-XNRI-7, Mitsui, NRCWE-006) or tangled CNT-T; in vitro exposure of peritoneal macrophages to 20, 10, 5 and 3 units of each CNT
• Main results:
  • Both CNT depleted resident peritoneal macrophages from 3 hours to 3 days compared with controls (macrophage disappearance reaction)
  • After CNT-7 macrophage numbers and proportions were almost restored by day 7; after CNT-T repopulation was slower and still incomplete at 30 days
  • No accumulation of CD68-positive macrophages in the omentum after either CNT, arguing against migration as the cause of the disappearance reaction
  • In vitro, both CNT reduced macrophage ATP dose-dependently, CNT-7 more at low doses
  • CNT-7, but not CNT-T, produced marked neutrophil influx and cytokine release in the peritoneal cavity
  • CCL2 and M-CSF were higher at 3 hours in CNT-7-treated rats than in CNT-T-treated and untreated rats
  • RNA-seq of macrophages purified at day 15 showed MHCIIhigh SPM gene signature enriched in CNT-7 versus CNT-T macrophages
  • Busulfan depletion of bone marrow progenitors abolished macrophage replenishment in CNT-7-treated rats and also affected it after CNT-T
  • Macrophages from CNT-T-treated rats showed more BrdU incorporation and more ki-67 transcript and protein than those from untreated or CNT-7-treated rats
• The authors' conclusion: The authors concluded that macrophage regeneration during the mesotheliomagenic response to CNT-7 depends on monocytes differentiating into MHCIIhigh inflammatory macrophages, while repopulation after non-mesotheliomagenic CNT-T involves proliferating MHCIIlow macrophages, and that depletion and repopulation characterize carcinogenic activity of particles and fibres

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Macrophage, Mesothelioma, Peritoneal Cavity, Carcinogenic.

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• Absence of carcinogenic response to multiwall carbon nanotubes in a 2-year bioassay in the peritoneal cavity of the rat — J. Muller, M. Delos, et al. (2009)
• Multi-walled carbon nanotubes injure the plasma membrane of macrophages — S. Hirano, S. Kanno, et al. (2008)
• Double-walled carbon nanotubes trigger IL-1β release in human monocytes through Nlrp3 inflammasome activation — E. Meunier, A. Coste, et al. (2012)
• Multiwalled carbon nanotube-induced pulmonary inflammatory and fibrotic responses and genomic changes following aspiration exposure in mice: A 1-year postexposure study — B.N. Snyder-Talkington, C. Dong, et al. (2016)

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