{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T18:03:20Z","timestamp":1776276200454,"version":"3.50.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013845","name":"Fondation contre le Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013845","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007546","name":"Agence Nationale de S\u00e9curit\u00e9 Sanitaire de l\u2019Alimentation, de l\u2019Environnement et du Travail","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007546","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004097","name":"Fondation ARC pour la Recherche sur le Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 MHCII<jats:sup>low<\/jats:sup> 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 MHCII<jats:sup>high<\/jats:sup> inflammatory macrophages. In contrast, the low inflammatory response induced by CNT-T was associated by the accumulation of self-renewing MHCII<jats:sup>low<\/jats:sup> 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.<\/jats:p>","DOI":"10.3389\/fimmu.2021.666107","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T08:15:27Z","timestamp":1623658527000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Monocytic Ontogeny of Regenerated Macrophages Characterizes the Mesotheliomagenic Responses to Carbon Nanotubes"],"prefix":"10.3389","volume":"12","author":[{"given":"Micaela","family":"Orsi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihaly","family":"Palmai-Pallag","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yousof","family":"Yakoub","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saloua","family":"Ibouraadaten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mich\u00e8le","family":"De Beukelaer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Bouzin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertrand","family":"Bearzatto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e9r\u00f4me","family":"Ambroise","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Luc","family":"Gala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Brusa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Lison","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Huaux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01060","article-title":"Polarization of Immune Cells in the Pathologic Response to Inhaled Particulates","volume":"11","author":"Ma","year":"2020","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/1750-1172-3-34","article-title":"Malignant Mesothelioma","volume":"3","author":"Moore","year":"2008","journal-title":"Orphanet J Rare Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3109\/17435390.2015.1009187","article-title":"Advances in Mechanisms and Signaling Pathways of Carbon Nanotube Toxicity","volume":"9","author":"Dong","year":"2015","journal-title":"Nanotoxicology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s12989-016-0158-0","article-title":"Mesothelioma Response to Carbon Nanotubes Is Associated With an Early and Selective Accumulation of Immunosuppressive Monocytic Cells","volume":"13","author":"Huaux","year":"2016","journal-title":"Part Fibre Toxicol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4513","DOI":"10.3390\/app10134513","article-title":"Carbon Nanotubes Under Scrutiny: Their Toxicity and Utility in Mesothelioma Research","volume":"10","author":"Orsi","year":"2020","journal-title":"Appl Sci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2008.111","article-title":"Carbon Nanotubes Introduced Into the Abdominal Cavity of Mice Show Asbestos-Like Pathogenicity in a Pilot Study","volume":"3","author":"Poland","year":"2008","journal-title":"Nat Nanotechnol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1038\/s41598-018-19521-9","article-title":"Macrophage Sensing of Single-Walled Carbon Nanotubes Via Toll-Like Receptors","volume":"8","author":"Mukherjee","year":"2018","journal-title":"Sci Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/17435390.2019.1651920","article-title":"Integration of Inflammation, Fibrosis, and Cancer Induced by Carbon Nanotubes","volume":"13","author":"Dong","year":"2019","journal-title":"Nanotoxicology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s12989-016-0150-8","article-title":"The Complex Cascade of Cellular Events Governing Inflammasome Activation and IL-1beta Processing in Response to Inhaled Particles","volume":"13","author":"Rabolli","year":"2016","journal-title":"Part Fibre Toxicol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3109\/17435390.2012.713527","article-title":"Length-Dependent Pleural Inflammation and Parietal Pleural Responses After Deposition of Carbon Nanotubes in the Pulmonary Airspaces of Mice","volume":"7","author":"Murphy","year":"2013","journal-title":"Nanotoxicology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01366","article-title":"The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy","volume":"9","author":"Chu","year":"2019","journal-title":"Front Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.02.024","article-title":"Tissue-Resident Macrophage Ontogeny and Homeostasis","volume":"44","author":"Ginhoux","year":"2016","journal-title":"Immunity"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2018.01.003","article-title":"The Biology of Serous Cavity Macrophages","volume":"330","author":"Bain","year":"2018","journal-title":"Cell Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00225","article-title":"Revisiting Mouse Peritoneal Macrophages: Heterogeneity, Development, and Function","volume":"6","author":"Cassado Ados","year":"2015","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.02.015","article-title":"Establishment and Maintenance of the Macrophage Niche","volume":"52","author":"Guilliams","year":"2020","journal-title":"Immunity"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.03.002","article-title":"Immunological Functions of the Omentum","volume":"38","author":"Meza-Perez","year":"2017","journal-title":"Trends Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfp100","article-title":"Absence of Carcinogenic Response to Multiwall Carbon Nanotubes in a 2-Year Bioassay in the Peritoneal Cavity of the Rat","volume":"110","author":"Muller","year":"2009","journal-title":"Toxicol Sci"},{"key":"B18","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1080\/08958370290084584","article-title":"Tumorigenicity of Cellulose Fibres Injected Into the Rat Peritoneal Cavity","volume":"14","author":"Cullen","year":"2002","journal-title":"Inhal Toxicol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e52553","DOI":"10.3791\/52553","article-title":"Busulfan as a Myelosuppressive Agent for Generating Stable High-Level Bone Marrow Chimerism in Mice","volume":"98","author":"Peake","year":"2015","journal-title":"J Vis Exp"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1534\/g3.119.400185","article-title":"Armor: An Automated Reproducible Modular Workflow for Preprocessing and Differential Analysis of RNA-Seq Data","volume":"9","author":"Orjuela","year":"2019","journal-title":"G3 (Bethesda)"},{"key":"B21","unstructured":"AndrewsS\n          Fastqc: A Quality Control Tool for High Throughput Sequence Data2010"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw354","article-title":"Multiqc: Summarize Analysis Results for Multiple Tools and Samples in a Single Report","volume":"32","author":"Ewels","year":"2016","journal-title":"Bioinformatics"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197","article-title":"Salmon Provides Fast and Bias-Aware Quantification of Transcript Expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nat Methods"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1113","article-title":"Ensembl 2019","volume":"47","author":"Cunningham","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1007664","article-title":"Tximeta: Reference Sequence Checksums for Provenance Identification in RNA-Seq","volume":"16","author":"Love","year":"2019","journal-title":"PLoS Comput Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616","article-title":"Edger: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1177\/1753425916651330","article-title":"Single-Cell Analysis Reveals New Subset Markers of Murine Peritoneal Macrophages and Highlights Macrophage Dynamics Upon Staphylococcus Aureus Peritonitis","volume":"22","author":"Accarias","year":"2016","journal-title":"Innate Immun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160486","article-title":"MHC II+ Resident Peritoneal and Pleural Macrophages Rely on IRF4 for Development From Circulating Monocytes","volume":"213","author":"Kim","year":"2016","journal-title":"J Exp Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1126\/science.1222453","article-title":"Carbon Nanotubes: Present and Future Commercial Applications","volume":"339","author":"De Volder","year":"2013","journal-title":"Science"},{"key":"B30","doi-asserted-by":"publisher","first-page":"264","DOI":"10.3390\/nano10020264","article-title":"Biocompatibility and Carcinogenicity of Carbon Nanotubes as Biomaterials","volume":"10","author":"Aoki","year":"2020","journal-title":"Nanomaterials (Basel)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-020-0654-0","article-title":"Banning Carbon Nanotubes Would be Scientifically Unjustified and Damaging to Innovation","volume":"15","author":"Heller","year":"2020","journal-title":"Nat Nanotechnol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/pin.12093","article-title":"Intraperitoneal Administration of Tangled Multiwalled Carbon Nanotubes of 15 Nm in Diameter Does Not Induce Mesothelial Carcinogenesis in Rats","volume":"63","author":"Nagai","year":"2013","journal-title":"Pathol Int"},{"key":"B33","doi-asserted-by":"publisher","first-page":"587","DOI":"10.2131\/jts.43.587","article-title":"Comparative Study for Carcinogenicity of 7 Different Multi-Wall Carbon Nanotubes With Different Physicochemical Characteristics by a Single Intraperitoneal Injection in Male Fischer 344 Rats","volume":"43","author":"Sakamoto","year":"2018","journal-title":"J Toxicol Sci"},{"key":"B34","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s12989-014-0059-z","article-title":"The Carcinogenic Effect of Various Multi-Walled Carbon Nanotubes (MWCNTS) After Intraperitoneal Injection in Rats","volume":"11","author":"Rittinghausen","year":"2014","journal-title":"Part Fibre Toxicol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.04.016","article-title":"Tissue-Specific Signals Control Reversible Program of Localization and Functional Polarization of Macrophages","volume":"157","author":"Okabe","year":"2014","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20182024","article-title":"Expression of Factor V by Resident Macrophages Boosts Host Defense in the Peritoneal Cavity","volume":"216","author":"Zhang","year":"2019","journal-title":"J Exp Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.42","article-title":"Does Niche Competition Determine the Origin of Tissue-Resident Macrophages","volume":"17","author":"Guilliams","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1038\/s41467-021-21778-0","article-title":"Recruited Macrophages That Colonize the Post-Inflammatory Peritoneal Niche Convert Into Functionally Divergent Resident Cells","volume":"12","author":"Louwe","year":"2021","journal-title":"Nat Commun"},{"key":"B39","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.immuni.2019.08.017","article-title":"Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche","volume":"51","author":"Bonnardel","year":"2019","journal-title":"Immunity"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7376","article-title":"Targeting the CCL2-CCR2 Signaling Axis in Cancer Metastasis","volume":"7","author":"Lim","year":"2016","journal-title":"Oncotarget"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010-0080OC","article-title":"Monocyte Chemoattractant Protein-1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8+ Cells","volume":"44","author":"Fridlender","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14343","article-title":"The Roles of Csfs on the Functional Polarization of Tumor-Associated Macrophages","volume":"285","author":"Jeannin","year":"2018","journal-title":"FEBS J"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0309","article-title":"Depletion of Tumor-Associated Macrophages With a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy","volume":"5","author":"Dammeijer","year":"2017","journal-title":"Cancer Immunol Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20171440","article-title":"Rapid Activation of Tumor-Associated Macrophages Boosts Preexisting Tumor Immunity","volume":"215","author":"Hoves","year":"2018","journal-title":"J Exp Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20082048","article-title":"Alternatively Activated Macrophage-Derived RELM-{Alpha} Is a Negative Regulator of Type 2 Inflammation in the Lung","volume":"206","author":"Nair","year":"2009","journal-title":"J Exp Med"},{"key":"B46","doi-asserted-by":"publisher","first-page":"15180","DOI":"10.1038\/s41598-018-33437-4","article-title":"Selective DNAM-1 Expression on Small Peritoneal Macrophages Contributes to CD4(+) T Cell Costimulation","volume":"8","author":"Takenaka","year":"2018","journal-title":"Sci Rep"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.03.009","article-title":"A Reservoir of Mature Cavity Macrophages That Can Rapidly Invade Visceral Organs to Affect Tissue Repair","volume":"165","author":"Wang","year":"2016","journal-title":"Cell"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300581","article-title":"Identification of a Tissue-Specific, C\/Ebpbeta-Dependent Pathway of Differentiation for Murine Peritoneal Macrophages","volume":"191","author":"Cain","year":"2013","journal-title":"J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.666107\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T08:15:33Z","timestamp":1623658533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.666107\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,14]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2021.666107"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.666107","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,14]]},"article-number":"666107"}}